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    CHK1 INHIBITOR, PHARMACEUTICAL COMPOSITION AND KIT UNDERSTANDING THE SUCH INHIBITOR.The present invention relates to the combination of a CHK1 inhibitor and a WEE1 inhibitor, as it has been found that the administration of a CHK1 inhibitor and a WEE1 inhibitor in combination can be used to treat cancer. Surprisingly, this combination shows synergistic potential, allowing the combination to be greater than the administration of any single inhibitor, where the CHK1 inhibitor is administered between the biologically effective dose and the maximum tolerated dose, and the WEE1 inhibitor is administered between the biologically effective dose and the maximum tolerated dose.
    公开号:BR112013011918A2
    申请号:R112013011918-7
    申请日:2011-11-16
    公开日:2020-08-25
    发明作者:Kurtis D. Davies；Stefan Gross
    申请人:Array Biopharma, Inc；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for "CHK1 INHIBITOR, PHARMACEUTICAL COMPOSITION AND KIT UNDERSTANDING THE SUCH INHIBITOR". BACKGROUND OF THE INVENTION
    FIELD OF THE INVENTION The present invention relates to a combination of a CHK1 kinase inhibitor and a WEE1 kinase inhibitor and methods of using it.
    DESCRIPTION OF THE STATE OF THE TECHNIQUE Checkpoint kinase 1 ("(CHK1") is a serine / threonine kinase. CHK1 regulates cell cycle progress and is a major factor in responding to DNA damage in a cell CHK1 inhibitors have been shown to sensitize tumor cells to a variety of genotoxic agents, such as chemotherapy and radiation. (Tse, Archie N., et a., "Targeting Checkpoint Kinase 1 in Cancer Therapeutics." Clin. Cancer Res. 13 (7) (2007) 1955-1960) It has been observed that many tumors are deficient in the G1 DNA damage checkpoint pathway, resulting in confidence in S and G2 checkpoints to repair DNA damage and survive (Jacnetka, James W. ,, et al., "Inhibitors of checkpoint kinases: From discovery to theclinic" Drug Discovery & Development Vol. 10, No. 4 (2007) 473-486). Checkpoints S and G2 are regulated by CHK 1. Inhibition of CHK1 has been shown to cancel checkpoints S and G2, thereby impairing DNA repair and er resulting in increased tumor cell death. However, non-cancer cells have a functioning 6G1 checkpoint, allowing DNA repair and survival. A primary target for CHK1 is phosphatase CDC25A, which is an activator of cyclin-dependent kinases ("CDKs"). When CHK1 phosphorylates CDC25A, the degradation of CDC25A is accelerated, which in turn slows down DNA replication and prevents entry into mitosis until the damage is repaired (Beck, Haldan, fetal, "Regulators of cyclin dependent kinases are crucial for maintaining genome integrity in S phase. "J. Cell Biol. Vol. 188, No. 5 (2010) 629-638). CHK1 inhibitors are known, see, for example, Publications
    Internacionall tion WO 2009/004329, International publication! WO - 2008/012635, International publication WO 2007/090493, International publication WO 2007/090494, International publication WO 2006/106326, International publication WO 2006/120573, International publication WO 2005/103036, International publication WO 2005 / 066163 and International Publication WO 03/028724.
    CHK1 inhibitors include PF-00477736 (also known as PF-477736) AZD7762, XL844, IC-83, CHIR-124, PD-321852, LY2603618, LY2606368 and SCH 900776.
    International publication Number WO 2009/140320 describes Ú compounds including (R) -N- (4- (3-aminopiperidin-1-11) -5-bromo-1H-pyrrolo [2,3- b] lpiridin-3-i ) nicotinamide (hereinafter "Compound 1") and (R) N- (4 (3-. aminopiperidin-1-yl) -5-bromo-1H-pyrrolo [2,3-b] pyridin-3-iN) isobutyramide (hereinafter "Compound 2"), (R) -N- (5-bromo-4- (3- (metulamino) piperidin-1-11) -1H- —pyrrole (2,3-b] lpiridin -3-iNnicotinamide (hereinafter "Compound 3"), (R) -N- (4- (3-aminopiperidin-1-iI) -5-bromo-1H-pyrrole (2,3-b] pyridin-3- il) -S-methylnicotinamide (hereinafter "Compound 4"), (R) -N- (4- (3-aminopiperidin-1-11) -5-bromo-1H-pyrrolo [2,3-b] pyridin- 3-yl) cyclopropanecarboxamide (hereinafter "Compound 5"), (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrolo [2,3-b] pyridin-3 -11) -3- methylbutanamide (hereinafter "Compound 6"), and (R) -N- (4- (3-aminopiperidin-1-yl) - 5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-cyclopropylacetamide (hereinafter "Compound 7"). Compounds 1, 2, 3, 4, 5, 6 and 7 (collectively "CHK1 926 inhibitors") are inhibitors of Oral CHK1.
    International publication Number WO 2009/151589 describes CHK1 inhibitors (hereinafter 'CHK1 inhibitors of application' 589 "). International publication Number WO 2009/151598 describes CHK1 inhibitors (hereinafter" CHK1 inhibitors of application ') 598 ").
    The wee1-like protein kinase ("WEE1") is a tyrosine kinase. WEE1 is inactivated in normal cells through phosphorylation and degradation during the M phase. WEE1 negatively regulates mitosis entry by
    The entry into mitosis is triggered by CDC25, which dephosphorylates Cdc2. X inhibition of WEE1 could result in abrogation of GM and uncontrolled entry into mitosis despite DNA damage. With the G2 / M checkpoint inactive, cells could become more susceptible to agents that damage DNA. In addition, healthy cells with a normal G; / S checkpoint can still survive.
    WEE1 inhibitors are known for yes, for example, see International Publication WO 2010/098367, International Publication WO 2010/067886, International Publication WO 2008/115742, International Publication WO 2008/115738, Publication international WO S 2007/126122, international publication WO 2007/126128, inter national publication WO 2004/007499 and publication of US patent application 2005/0037476: WEE1 inhibitors include MK-1775, PD-166285 (also co - - known as PDO166285) and PF-00120130. There remains a need for treatment of diseases, particularly hyperproliferative diseases such as cancer.
    SUMMARY OF THE INVENTION It has been found that the administration of a CHK1 inhibitor and a WEE1 inhibitor in combination can be used to treat cancer. Surprisingly, this combination shows synergistic potential, allowing the combination to be greater than the administration of any single inhibitor. In one aspect, the present invention provides for the use of a CHK1 inhibitor in combination with a WEE1 inhibitor.
    Another aspect of the present invention provides for the use of a CHK1 inhibitor in combination with a WEE1 inhibitor to treat a hyperproliferative disease such as cancer.
    Another aspect of the present invention provides for the use of a CHKI1 inhibitor for the manufacture of a medicament for combined use Aanm 1m inhibited- it IAIEEDCAS nm treats Adao ma dasasnmnoa hinncnralifaratnhia
    Another aspect of the present invention provides a pharmaceutical composition comprising a CHK1 inhibitor and a WEE1 inhibitor. Another aspect of the present invention provides a pharmaceutical composition B for the treatment or prevention of a hyperproliferative disease, such as cancer, comprising a CHK1 inhibitor and a WEE1 inhibitor.
    Another aspect of the present invention provides a method for treating or preventing a hyperproliferative disease, such as cancer, by administering a CHK1 inhibitor in combination with a WEE1 inhibitor.
    Another aspect of the present invention provides a method for treating or preventing a hyperproliferative disease, such as cancer, by administering one. CHK1 inhibitor in combination with a WEE1 inhibitor, where the inhibitor. CHK1 pain is administered between the biologically effective dose and the "maximum tolerated dose, and the WEE1 inhibitor is administered between the biologically effective dose and the maximum tolerated dose.
    Another aspect of the present invention provides a method for treating or preventing a hyperproliferative disease, such as cancer, comprising administering to a mammal in need of an effective amount of a CHK1 inhibitor in combination with an effective amount of an inhibitor.
    deWEE '.
    Another aspect of the present invention provides a kit comprising a CHK1 inhibitor and a WEE1 inhibitor.
    Another aspect of the present invention provides a kit comprising a CHK1 inhibitor and a WEE1 inhibitor for use in combination to treat or prevent a hyperproliferative disease, such as cancer.
    Another aspect of the present invention provides a Kit that comprises separate containers of a CHK1 inhibitor and a WEE1 inhibitor for use in combination to treat or prevent a hyperproliferative disease, such as cancer.
    Another aspect of the present invention provides a kit comprised of a nanmarmed nanometer and a minimalist Fpamamamanã: vial in the earmhalamcam, like a cancer cell, comprising in a container a pharmaceutical composition comprising an effective amount of a CHK1 inhibitor and in a second container a pharmaceutical composition comprising an effective amount of a WEE1 inhibitor.
    BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the cell viability of HEL92.1.7 cells after treating with a CHK1 inhibitor. Figure 2 shows the cell viability of HEL92.1.7 cells after treating with a WEE1 inhibitor. Figure 3 shows Caspase 3/7 activity after treatment with a CHK1 inhibitor. ”Figure 4 shows Caspase 3/7 activity after treatment with a WEE1 inhibitor. 'Figure 5 shows a Cdk2 pY 15 phosphorylation experiment. Figure 6 shows a Cdc2 pT14 / Y15 phosphorylation experiment. Figure 7 shows phosphorylation experiment H2A.X pS139. Figure 8 shows a CHK1 pS345 phosphorylation experiment. Figure 9 shows an HEL92.1.7 cell nucleoside incorporation experiment.
    DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments of the invention. Although the invention is described in combination with the listed modalities, it will be understood that they are not intended to limit the invention to those modalities. On the contrary, the invention aims to cover all alternatives, modifications and equivalents, which can be included in the scope of the present invention as defined by the claims. A person skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is not limited to an order, including, but not limited to defined terms, use of the term, described techniques, or the like, that order has control.
    DEFINITIONS 'The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid leukemia or malignancies. More specific examples of such cancers include squamous cell cancer (eg epithelial squamous cell cancer), lung cancer including small cell lung cancer, lung cancer. non-small cell ("NSCLC"), lung adenocarcinoma and squamous carcinoma of the lung, peritoneum cancer, hepatocellular cancer, stomach or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer , bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine or endometrial carcinoma, salivary gland carcinoma, kidney or kidney cancer, prostate cancer, vulva cancer, thyroid cancer , liver carcinoma, and carcinoma, penile carcinoma, skin cancer including melanoma, and head and neck cancer.
    The term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described here and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates including humans.
    The phrase "pharmaceutically acceptable" indicates that the substance or composition is chemically and / or toxicologically compatible, with the other ingredients comprising a formulation, and / or the mammal being treated with it.
    The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound described herein that, when air, improves, or eliminates one or more symptoms of the specific disease, condition or disorder, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition or disorder described here.
    The amount of "a compound that will correspond to such an amount will vary depending on factors such as the specific compound, disease condition and its severity, the identity (eg weight) of the mammal in need of treatment, however it can nevertheless be routinely determined by a person skilled in the art.
    The effective amount may be at or above the biologically effective amount, but at or below the maximum tolerated dose.
    The effective amount may be at the maximum tolerated dose.
    In the case of cancer, an effective amount of the inhibitor can reduce the number of "cancer cells; reduce the size of the tumor; inhibit (that is, decrease to some extent and preferably stop) cancer cell infiltration into peripheral organs; 'inhibit (i.e., decrease to a certain extent and preferably stop) tumor metastasis, inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with cancer.
    To the extent that inhibitor can prevent growth and / or exterminate existing cancer cells, it can be cytostatic and / or cytotoxic.
    For cancer therapy, effectiveness can be measured, for example, by assessing the time for disease progress
    çca ("TTP") and / or determine the response rate ("RR"). The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventive measures.
    For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, symptom relief, decrease in disease extent, stabilized state (ie, does not worsen) of disease, delay or decrease in disease progress, improvement in disease status, and remission (either partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment.
    Those in need of treatment include those already with the condition or disorder, as well as those likely to have the condition
    The present invention provides for the use of a CHK1 inhibitor in combination with the WEE1 inhibitor in the treatment of a hyperproliferative disease.
    In certain embodiments, the hyperproliferative disease is cancer. "The exploration of cell cycle control is a fundamental aspect that tumor cells are based on for growth.
    One mechanism by which this can be accomplished is the manipulation of cell cycle checkpoints and DNA damage repair.
    The evidence suggests that tumor cells may evolve to become refractory to chemotherapy by hyperactivating DNA damage repair at checkpoint G2 / M, a cell process that is dependent on CHK1. Inhibition of CHK1 removes this survival route. The.
    CHK1 kinase is involved in cell cycle checkpoint activation and DNA repair in response to DNA damage.
    Therefore, 'CHL1 inhibitors have demonstrated preclinical activity in combination with DNA damaging agents.
    CHK1 is also known to be critical for cell cycle progress in undisturbed cells (that is, in the absence of exogenous DNA damage), and inhibition of single agent CHK1 is antiproliferative in cancer cell lines cultured in vitro (see Example 2 and Figures 1 and 2). A screening of synthetic lethality siRNA was performed in combination with a CHK1 inhibitor. In courses of this sorting conducted on PC3, LNCaP and AS49 cell lines, Wee1 kinase siRNAs demonstrated the ability to increase the antiproliferative effect of a CHK1 inhibitor (see Example 1). Follow-up studies were carried out on the HEL92.1.7 cell line. this strain was shown to be sensitive to both CHK1 inhibition and WEE1 inhibition in terms of cell proliferation (see Example 2 and Figures 1 and 2). When the CHK1 inhibitor and the WEE1 inhibitor were combined in a matrix mode, a synergistic effect was observed (see Example 2). The combination of the two inhibitors resulted in up to approximately four times increased antiproliferative activity O a O A A a WINGS Ad o a NA AD dosed as single agents (see Example 3 and Figures 3 and 4). In correlation with antiproliferative synergy, the combination of inhibitors resulted in up to approximately five times the increase in apoptosis compared to what would be expected from additivity (see Example 3). CHK1 activity leads to the sequestration and degradation of CDC25 phosphates, thereby promoting inhibitory phosphorylation of CDKs. Wee1 kinase directly phosphorylates CDKs in the same residues. Cdk2 and Cdc2 are CDKs that are believed to control mainly S-phase progress and mitotic input, respectively. As expected, both the CHK1 inhibitor and the WEE1 inhibitor lead to reduced inhibitory phosphorylation of Cdk2 and Cdc2, and the combination further decreased phosphorylation (see "Example 4 and Figures 5 and 6). the combination of a CHK1 inhibitor and a WEE1 inhibitor leads to a strong disinhibition of Cdk2 and 'Cde2.
    The disinhibition of CDKs has been shown to result in S-phase DNA damage, probably a result of deregulation of triggering DNA replication origins (Beck, supra). Accordingly, both the CHK1 inhibitor and the WEE1 inhibitor resulted in increased phosphorylation of H2A.X S139 (a biochemical marker for DNA damage), and the combination of the inhibitors additionally increased phosphorylation ( see Example 5 and Figure 7). DNA damage leads to cell cycle checkpoint activation. In correlation with the observed DNA damage, both the CHK1 inhibitor and the WEE1 inhibitor increased CHK1 S345 phosphorylation (see Example 5 and Figure 8). In addition, a combination of low concentrations of the CHK1 inhibitor and WEE1 inhibitor led to increased phosphorylation of CHK1 S345.
    The DNA damage associated with CDK disinhibition has been suggested to be the result of replication fork collapse and / or premature entry into mitosis. These two events result in the inhibition of S-phase DNA synthesis in support of this, both the CHK1 inhibitor and the WEE1 inhibitor Mama A in UIA ala nftiana dm FIA in the fame mililmam Mn mam mafsiim was
    One embodiment provides for the use of a CHK1 inhibitor in combination with a WEE1 inhibitor. Another modality provides for the use of a CHK1 inhibitor in combination with a WEE1 inhibitor to treat a hyperproliferative disease such as cancer. In an additional embodiment, the use includes the use of a DNA damage agent.
    Another embodiment provides for the use of a pharmaceutical composition comprising a CHK1 inhibitor in combination with a pharmaceutical composition comprising a WEE1 inhibitor to treat a hyperproliferative disease, such as cancer. Another embodiment provides a use of a pharmaceutical composition comprising an effective amount of "a CHK1 inhibitor in combination with a pharmaceutical composition comprising an effective amount of a WEE1 inhibitor to treat" a hyperproliferative disease, such as cancer. In an additional embodiment, I use the use of a DNA damage agent.
    Another modality provides for the use of a CHK1 inhibitor for the manufacture of a drug for use combined with a WEFE1 inhibitor in the treatment of a hyperproliferative disease, such as cancer.
    Another embodiment provides a pharmaceutical composition comprising a CHK1 inhibitor and a WEE1 inhibitor. Another embodiment provides a pharmaceutical composition comprising an effective amount of a CHK1 inhibitor and an effective amount of a WEE1 inhibitor. In an additional embodiment, the composition also includes an effective amount of a DNA damage agent.
    Another embodiment provides a pharmaceutical composition for the treatment or prevention of a hyperproliferative disease, such as cancer, comprising a CHK1 inhibitor and a WEE1 inhibitor. Another modality provides a pharmaceutical composition for the treatment or prevention of a hyperproliferative disease, such as cancer, comprising an effective amount of a CHK1 inhibitor and an effective amount of an Am TAICDIA Dn inhibitor in addition to the adintíasal nn ammmmaninta imenhAnn immbhi love
    Another aspect of the present invention provides a method for treating or preventing a hyperproliferative disease, such as cancer, by administering a CHK1 inhibitor in combination with a WEE1 inhibitor. Another aspect of the present invention provides a method for treating or preventing a hyperproliferative disease, such as cancer, by administering an effective amount of a CHK1 inhibitor in combination with an effective amount of a WEE1 inhibitor. In an additional embodiment, the method also includes delivering an effective amount of a DNA damage agent.
    Another modality provides a method to treat or prevent a hyperproliferative disease, such as cancer, by administering a CHK1 inhibitor in combination with a WEE1 inhibitor, in which the CHK1 inhibitor is administered at or between the biologically effective dose and the tolerated dose. maximum, and the WEE1 inhibitor is administered between the biologically effective dose and the maximum tolerated dose. In an additional embodiment, the method also includes administering an effective amount of a DNA damage agent.
    Another embodiment provides a method for treating or preventing a hyperproliferative disease, such as cancer, comprising administering to a mammal in need of an effective amount of a CHK1 inhibitor in combination with an effective amount of a WEE1 inhibitor. In an additional embodiment, the method also includes administering an effective amount of a DNA damage agent.
    One embodiment provides a kit comprising a CHK1 inhibitor and a WEE1 inhibitor. In an additional embodiment, the kit also contains a DNA damage agent.
    The kit may comprise a container comprising the combination. Suitable containers include, for example, bottles, flasks, rings, blister packs, etc. The container can be formed from a variety of materials such as glass or plastic. The container may contain the combination that is effective in treating the condition and may have an access port (AmA mana Dm mo an tra dio md amine nm imi ami ami in the skin in the skin). - The kit may also comprise a label or packaging insert in or associated with the container.
    The term "packaging insert" is Ú used to refer to instructions usually included in commercial packaging of therapeutic products, which contain information on the indications, use, dosage, administration, contraindications and / or alerts regarding the use of such therapeutic products.
    In one embodiment, the label or packaging inserts indicate that the composition comprising the CHK1 inhibitor and / or the WEE1 inhibitor can be used to treat a disorder.
    The label or packaging insert may also indicate that the composition can be used to treat other disorders. - In certain embodiments, the kits are suitable for the supply of solid oral forms of the CHK1 inhibitor and the WEE1 inhibitor,] as tablets or capsules.
    Such a kit preferably includes a number of unit doses.
    Such kits may include a card with the dosages oriented in the order of their intended use.
    An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.
    If desired, a memory aid can be provided — for example, in the form of numbers, letters or other markings or with a calendar insert, designating the days in the treatment program in which dosages can be administered .
    According to another embodiment, a kit can comprise (a) a first container with a CHK1 inhibitor contained therein; and (b) a second container with a WEE1 inhibitor contained therein.
    Alternatively, or in addition, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution and dextrose solution.
    It may also include other materials desirable from a user and commercial point of view, including medial information, including the CHK1 inhibitor and the WEE1 inhibitor. For example, the kit may further comprise guidelines for the simultaneous, sequential or separate administration of the CHK1 inhibitor and the WEE1 inhibitor to a patient in need of it.
    In certain other embodiments, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil package, however, the compositions may also be contained in a single, undivided container. In certain embodiments, the kit includes guidelines for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (for example, oral and parenteral), are administered at different dosage intervals, or when the titration of the components of the combination is desirable by the prescribing physician.
    Another aspect of the present invention provides a kit comprising separate containers of a CHK1 inhibitor and a WEE1 inhibitor for use in combination to treat or prevent a hyperproliferative disease such as cancer. In an additional modality, the kit also contains a DNA damage agent.
    Another aspect of the present invention provides a kit comprising separate containers in a single-pack pharmaceutical composition for use in combination to treat or prevent a hyperproliferative disease such as cancer, which comprises in a container a pharmaceutical composition comprising an effective amount of a a CHK1 inhibitor and in a second container a pharmaceutical composition comprising an effective amount of a WEE1 inhibitor. In an additional way, the kit also contains a DNA damage agent.
    Another modality provides a kit comprising: (a) a CHK1 inhibitor, and (b) a WEE1 inhibitor, mm am mia mesh amphim mara Eemimr mir mama am irma Alma mas 5
    Another embodiment provides a kit comprising: - (a) a CHK1 inhibitor, (b) a WEE1 inhibitor, and '(c) a DNA damaging agent, for use in combination to treat or prevent a hyperproliferative disease , such as cancer.
    Another embodiment provides a kit comprising: (a) a pharmaceutical composition comprising a CHK1 inhibitor, and (b) a pharmaceutical composition comprising a WEE1 inhibitor, - for use in combination to treat or prevent a hyperproliferative disease, such as like cancer.
    Another embodiment provides a kit comprising: (a) a pharmaceutical composition comprising a CHK1 inhibitor, (b) a pharmaceutical composition comprising a WEE1 inhibitor, and (c) a pharmaceutical composition comprising a DNA damaging agent, for use in combination to treat or prevent a hyperproliferative disease, such as cancer.
    Another embodiment provides a kit comprising: (a) a pharmaceutical composition comprising an effective amount of a CHK1 inhibitor, and (b) a pharmaceutical composition comprising an effective amount of a WEE1 inhibitor, for use in combination for treat or prevent a hyperproliferative disease, such as cancer.
    Another modality provides a Kit that comprises: AA a a a a Em o E a mi a E a A aiming at a wired wire
    (b) a pharmaceutical composition comprising an effective amount of a WEE1 inhibitor, and (c) a pharmaceutical composition comprising an effective amount of a DNA damaging agent, for use in combination to treat or prevent a hyperproliferative disease, such as cancer. In certain embodiments of the present invention, the CHK1 inhibitor is selected from the group consisting of CHK1 '926 inhibitors. In certain embodiments of the present invention the CHK1 inhibitor is selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 and Compound 7. In certain embodiments of the present invention, the inhibitor of CHK1 is Compound 1. In certain embodiments of the present invention, the CHK1 inhibitor is Compound 2. In certain embodiments of the present invention, the CHK1 inhibitor is Compound 3. In certain embodiments of the present invention, the CHK1 inhibitor is Compound 4. In certain embodiments of the present invention, the CHK1 inhibitor is Compound 5. In certain embodiments of the present invention, the CHK1 inhibitor is Compound 6. In certain embodiments of the present invention, the CHK1 inhibitor is Compound 7.
    In certain embodiments of the present invention, the CHK1 inhibitor is selected from the group consisting of CHK1 '926 inhibitors, PF-00477736, AZD7762, XL844, IC-83, CHIR-124, PD-321852, LY2603636, LY2606368 and SCH 900776 In certain embodiments of the present invention, the CHK1 inhibitor is selected from the group consisting of PF-00477736, AZD7762, XL844, IC-83, CHIR-124, PD-321852, LY2603618, LY2606368 and SCH 900776. In certain embodiments of present invention, the CHK1 inhibitor is selected from the group consisting of CHK1 inhibitors “926, PF-00477736, AZD7762, XL844, IC-83, and CHIR-124. In certain embodiments of the present invention, the CHK1 inhibitor is selected from the group consisting of PF-00477736, AZD7762, XL844, IC-83, and CHIR-124. In certain mm aimilailataa & indaidar MI ISA naeunlb mo Iinlhidlmeno in CLIN A INÍ5 of CHK1 of the application “598. In certain embodiments, the CHK1 inhibitor is a CHK1 inhibitor of the '589 application. In certain embodiments, the CHK1 inhibitor is a CHK1 inhibitor of the “598. Ú An oral CHK1 inhibitor is a CHK1 inhibitor that can be administered orally. When the CHK1 inhibitor is administered orally, it can be formulated as a pill, hard or soft capsule, tablet, lozenge, aqueous or oily suspension, emulsion, dispersible granules or powders, syrup, elixir, etc., with a pharmaceutically acceptable excipient or vehicle. CHK1 '926 Inhibitors are oral CHK1 inhibitors. In certain embodiments of the present invention, the WE-E1 inhibitor is selected from the group consisting of MK-1775, PD-166285 and PF-. 00120130. In certain embodiments of the present invention, the WE-E1 inhibitor is selected from the group consisting of MK-1775 and PD-166285. In: certain embodiments of the present invention, the WEE1 inhibitor is MK-1775. In certain embodiments of the present invention, the WEE1 inhibitor is PD-
    166285. In certain embodiments of the present invention, the WEE1 inhibitor is PF-00120130. An oral WEE1 inhibitor is a WEE1 inhibitor that can be administered orally. When the WEE1 inhibitor is administered orally, it can be formulated as a pill, hard or soft capsule, tablet, lozenge, aqueous or oily suspension, emulsion, dispersible powders or granules, syrup, elixir, etc., with a pharmaceutically acceptable excipient or vehicle, MK-1775 is an oral WEE1 inhibitor. Inhibitors of WEE1 and CHK1 can be administered before, concomitantly with or after administration of each other. The sequential administration of each agent can be close in time or remote in time. Typically, the CHK1 and WEE1 inhibitors are individually formulated by mixing at room temperature at the appropriate pH, and in the desired purity grade, with physiologically acceptable vehicles, that is, they are not unsafe to EmASBinenA mam dassamana to AmIASImiramíAS depends mainly of the specific use and concentration of compound, po-. also it can vary anywhere from approximately 3 to approximately 8. The formulation in an acetate buffer at pH 5 is an appropriate modality. In one embodiment, formulations comprising compounds of the invention are sterile. The compounds will be stored commonly as a solid composition, although lyophilized formulations or aqueous solutions are acceptable. Compositions comprising CHK1 and WEE1 inhibitors will be formulated, dosed and administered in a manner compatible with good medical practice. Factors for consideration in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the place of administration, the method of administration, the schedule of administration, and 'other factors known to doctors.
    Inhibitors can be administered in any convenient administrative form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, adhesives, etc. Such compositions may contain conventional components in pharmaceutical preparations, for example, diluents, vehicles, pH modifiers, sweeteners, bulking agents, and additional active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
    Generally, the initial pharmaceutically effective amount of the parenterally administered inhibitor per dose will be in the range of approximately 0.01 to 100 mg / kg / day, for example, approximately 0.1 to 20 mg / kg of the patient's body weight per day, with the typical starting range of inhibitor compound used being 0.3 to 15 mg / kg / day. Oral unit dosage forms, such as tablets and capsules, may contain approximately 25 to approximately 1000 mg of the inhibitor.
    fim im bh ialmeam Alm PFUVCILA - VAIDCIIA mmcisnmm mer and aline mined topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and if desired for local treatment, intralesional administration.
    Parenteral infusions include intramuscular, intravenous,, intra-arterial, intraperitoneal or subcutaneous administration.
    An example of an appropriate oral dosage form is a tablet containing approximately 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of the compound inhibitor with approximately 90 to 30 mg of anhydrous lactose, approximately 5 to 40 mg of croscarmellose sodium, approximately 5 to 30 mg of polyvinyl pyrrolidone ("PVP") K30, and approximately 1 to 10 mg of magnesium stearate.
    The powdered ingredients are first mixed together and then mixed i with a PVP solution.
    The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into a tablet using conventional equipment.
    An aerosol formulation! it can be prepared by dissolving the inhibitor, for example, 5 to 400 mg in an appropriate buffer solution, for example, a phosphate buffer, adding a toner, for example, a salt such as sodium chloride, if wanted.
    The solution is typically filtered, for example, using a 0.2 mm filter.
    cron, to remove impurities and contaminants.
    Another formulation can be prepared by mixing an inhibitor and a vehicle or excipient.
    Suitable vehicles and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
    Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al.
    Remington: The Science and Practice of Pharmacy.
    Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.
    Handbook of Pharmaceutical Excipients.
    Chicago, Pharmaceuticals Press, 2005. Formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, anti-oxidants, opaque agents, glidants, auxiliary means of processing,
    elegant drug preparation (i.e., a CHK1 inhibitor and / or an WE-: E1 inhibitor or pharmaceutical composition thereof) or assist in the manufacture of the pharmaceutical product (i.e., medicine).
    The CHK1 inhibitor and WEE1 inhibitor must be dosed at least one level to achieve the desired biological effect. In this way, an effective dosing regimen will dose at least a minimum amount that achieves the desired biological effect, or biologically effective dose. However, the dose should not be so high as to outweigh the benefit of the biological effect with unacceptable side effects. Therefore, an effective dosing regimen will dose no more than the maximum tolerated dose ("BAT"). The maximum tolerated dose is defined as the highest dose. which produces an acceptable incidence of dose limit toxicities ("DLT"). Doses that cause an unacceptable rate of DLT are considered 'not tolerated. Typically, the BAT for a specific program is established in phase | clinical experiments. are normally conducted in patients by starting at a safe starting dose of 1/10 of the severe toxic dose ("STD10") in rodents (on a mg / m basis ) and providing patients in groups of three, increasing the dose according to a modified Fibonacci sequence in which increasingly higher steps of increase have increasingly decreasing relative increments (for example, dose increases of 100%, 65%, 50%, 40% and 30% at 35% later). The dose increase continues in groups of three patients until an unacceptable dose is reached. The next lowest dose level that produces an acceptable rate of DLT is considered to be the BAT.
    In addition, BAT varies depending on the specific inhibitor, species and dosing program. For example, dosing only on day one versus days one and two versus days one through three in a dosing cycle of seven, fourteen, twenty-one or twenty-eight days can all have different BATs. In addition, the dosage of a CHK1 inhibitor individually or in combination with a DNA damaging agent may have MTDs of effective dosage need to dose the inhibitor high enough to be - biologically effective.
    The dosage on day one can only reach the biologically effective dose, but it may not be long enough to prevent damaged DNA repair cells.
    Alternatively, dosing days one through three may dose long enough, but may not dose high enough to achieve the biologically effective dose.
    This may be due to the dosage MTD for three days being lower than the biologically effective dose.
    Thus, an effective dosing program will have an MTD equal to or greater than the biologically effective dose.
    Typically to treat cancer, patients are dosed in the BAT of a specific compound | I stay so that the maximum benefit in treatment can be achieved. . In one embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is an inhibition of 80% or greater in p- 'CHK1. In another embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is an inhibition of 80% or greater in pCHK1 after administration of a DNA damage agent (in relation to the administration of the DNA damage agent alone). In another embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is an inhibition of 90% or greater in p-CHK1. In another embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is a 90% or greater inhibition in pCHK1 after administration of a DNA damage agent (in relation to the administration of the DNA damage agent alone). In another embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is 95% or greater inhibition in p-CHK1. In another embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is 95% or greater inhibition in pCHK1 after administration of a DNA damage agent (in relation to the administration of the DNA damage agent alone). In another embodiment of the present invention, the decreased biological effect of a CHK1 inhibitor is an inhibition of 668% or greater in p-
    that of a CHK1 inhibitor is an inhibition of 66% or greater in p-cdc2 after - administration of a WEE1 inhibitor (in relation to the administration of the WEE1 inhibitor alone). In another embodiment of the present invention, the desired biological effect of a CHK1 inhibitor is a 66% or greater inhibition in p-cdc2 after administration of a DNA damage agent (in relation to the administration of the DNA damage agent alone ). In one embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is an inhibition of 80% or greater in p-cdc2. In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is an inhibition of 80% or greater in p-cde2 after administration of a DNA damaging agent (in relation to the administration of the damaging agent of DNA alone).
    In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is an inhibition of 90% or greater in p-cdc2. In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is an inhibition of 90% or greater in p-cdc2 after administration of a DNA damage agent (in relation to the administration of the damage agent of DNA alone).
    In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is 95% or greater inhibition in p-cdc2. In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is a 95% or greater inhibition in p-cdc2 after administration of a DNA damaging agent (in relation to the administration of the damaging agent of DNA alone).
    In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is an inhibition of 66% or greater in p-cdc2. In another embodiment of the present invention, the desired biological effect of a WEE1 inhibitor is an inhibition of 66% or greater in p-cdc2 after administration of a CHK1 inhibitor (in relation to administration of the CHK1 inhibitor alone). In another embodiment of the present invention, the thin layered effect of 11659 inikhbitor of WEE1 is a 66% or greater inhibition in relation to the administration of the DNA damaging agent alone). . In one embodiment, the CHK1 inhibitor is administered at or between the biologically effective dose and the maximum tolerated dose of the inhibitor. In one embodiment, the CHK1 inhibitor is administered at the maximum tolerated dose of the inhibitor.
    In one embodiment, the WEE1 inhibitor is administered at or between the biologically effective dose and the maximum tolerated dose of the inhibitor. In one embodiment, the WEE1 inhibitor is administered at the maximum tolerated dose of the inhibitor.
    Some data for the MTD of MK-1775 in combination with gemcitabine, carboplatin and cisplatin have been published (see Leijen, S., and others. "A phase | pharmacological and pharmacodynamic study of MK-1775, a Wee1 tyrosine kinase inhibitor, in monotherapy and combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. ”J Clin Oncol. 28: 15s (2010) (supl; abstract 3067); 2010 ASCO Annual Meting, and Schellens, JH, and others." A phase | and pharmacological study of MK-1775, a Wee1 tyrosine kinase inhibitor, in both monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. "J. Clin. Oncol. 27: 15s ( 2009) (supl; abstract 3510); 2009 AS-CO Annual Meeting) The MTD of MK-1775 as a single dose in combination with gemcitabine (1000 mg / m ) Has been reported as 200 mg. -1775 as a single dose in combination with cisplatin (75 mg / m ) Has been reported as 200 mg. MK-1775 BAT as a single dose a in combination with carboplatin (AUC 5) was reported as 325 mg. OMTD of MK-1775 as a multiple dose (BID day 1, BID day 2, and QD day 3) in combination with gemcitabine (1000 mg / m ) Was reported as 50 mg BID day 1, 25 mg BID day 2 and 25 mg QD day 3. The MTD of MK-1775 as a multiple dose (5 BID doses) in combination with cisplatin (75 mg / m ) was reported as 125 mg, with the experiment in progress. The MTD of MK-1775 as a multiple dose (5 BID doses) in combination with carbonatin (UC 5X was renamed as 2995 hands with 60 steps in progress.
    In certain embodiments of the present invention, doses of inhibitor. CHK1 and / or WEE1 pain can be divided into two or more daily administrations (ie BID dosage means twice daily). Multiple administrations can be spaced during the day. This can also include multiple administrations on multiple days.
    In certain embodiments, the invention provides a use or composition to treat cancer. In certain embodiments, the invention provides a method for treating cancer. More particularly, cancers that can be treated by the compositions and methods of the invention include, but are not limited to: Soft Tissue Cancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and 2 teratoma ; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), U alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (Wilm's tumor adenocarcinoma [nephroblast-mail, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma , embryonic carcinoma, tera- toccinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma <Ewino's sarcoma Malian lymphoma (reticulum cell sarcoma)
    (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondro- myxofibroma, osteoid osteoma and giant cell tumors; Nervous System: skull (osteoma, hemangioma, granuloma, xanthoma, deforming osteitis), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astro-cytoma, medulloblastoma, glioma, ependymoma, germinoma [inealomal], gli- multiforme oblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord: neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadeno-carcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granular tissue cell tumors, tumors of granular tissue cell Sertoli-Leydig cell, .dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina] (clear cell carcinoma, squamous cell carcinoma, botryoscopic sarcoma of embryosarcoma ], fallopian tubes (carcinoma); Hematologic: blood and bone marrow (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), disease of Hodgkin, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, soft dysplasic nevi, lipoma, angio ma, dermatofibroma, keloid, psoriasis; and Adrenal glands: neuroblastoma. The term "cancer cell" as provided herein includes a cell afflicted by any of the conditions identified above.
    In certain embodiments of the present invention, cancer is selected from colorectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, glioma, ovarian cancer, metastatic breast cancer, pancreatic cancer , hepatobiliary cancer (including hepatocellular cancer, bile duct cancer and cholangiocarcinoma), gastric cancer, testicular cancer, squamous cell carcinoma and necoco lencemia (including myeloid levcemia or lineal leukemia
    foma (including mantle cell lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma) and prostate cancer. In certain embodiments of the present invention, the cancer is a solid tumor cancer. In certain embodiments of the present invention, cancer is selected from pancreatic cancer, ovarian cancer and colorectal cancer. In certain embodiments of the present invention, cancer is selected from colorectal cancer (including Ras mutations), lung cancer. small cell, non-small cell lung cancer and glioma.
    In certain embodiments of the present invention, cancer is selected from non-small cell lung cancer, ovarian cancer, metastatic breast cancer, pancreatic cancer, hepatobiliary cancer (including hepatocellular cancer, bile duct cancer and cholangiocarcinoma ) and cancer: gastric.
    In certain embodiments of the present invention, cancer is selected from colorectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, ovarian cancer, hepatobiliary cancer (including hepatocellular cancer, cancer of the lung) bile duct and cholangiocarcinoma), gastric cancer, testicular cancer and head and neck squamous cell carcinoma.
    In certain embodiments of the present invention, cancer is selected from leukemia (including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia and chronic lymphoid leukemia), lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma and lymphoma not —Hodgkin) and prostate cancer.
    In certain embodiments, the combination further includes combining with a DNA damaging agent. DNA damaging agents include GemzarO & (gemcitabine), CamptosarO (irinotecan or CPT-11), Temo-darO (temozolomide), XelodaO (capecitabine), Hycamtin & (topotecan), cis-platinum, Eloxatin & (oxaliplatin), Paraplatin & Paraplatin carboplatin), camptothecin, ara-C (cytarabine)., 5-FU (fluorouracil)) CvytoxanO (cyclophosphamide), Etopo-
    cin PFSO & or Adriamycin RDFO (doxorubicin), daunorubicin, Alimta & - (pemetrexed), and radiation. In certain embodiments, the DNA damaging agent is selected from the group consisting of gemcitabine, irinotecan, S temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU. In certain embodiments, the DNA damaging agent is selected from genitabine, irinotecan, temozolomide and capecitabine. In certain embodiments, the DNA damaging agent is selected from gemcitabine, irinotecan, cisplatin, oxaliplatin, carboplatin and cytarabine. In certain embodiments, the DNA damaging agent is selected from gemcitabine and irinotecan. The DNA damaging agent is administered in its approved or recommended dose. In one embodiment, the DNA damaging agent is administered at the maximum tolerated dose. In certain embodiments, the DNA damaging agent is selected from the group consisting of cisplatin, oxaliplatin and carboplatin. In certain embodiments, the DNA damaging agent is genitabine. In an additional embodiment, the DNA damaging agent is cytarabine.
    EXAMPLES To illustrate the invention, the following examples are included. However, it should be understood that these examples do not limit the invention and are only intended to suggest a method of putting the invention into practice. Example 1 SIRNAs for Wee1 increase the antiproliferative activity of an inhibitor of
    25. Ch A synthetic lethality screening using SiRNAs for 197 genes (3 siRNAs per gene) was performed on PC3, LN-CaP cell lines (2 independent experiments) and A549. The cells were transfected inversely with siRNAs in 96-well plates, treated with compound2 or vehicle one day after and then analyzed by CellTiter Blue viability assay three days after treatment. The data shown are the values representing percentage of control with the control being the average of all values for each individual plate. [| Pce3 | EINnCcaP () |] LNCaPQ: 2 | A | 8 | 36 | and | NA | 64 | 55 | 88 | B | es | 8 | 103 | 100 | & | 8 | 132 Le 1106 | 75 48 64 Example 2 Chk1 inhibition and Wee inhibition combine to inhibit cell proliferation HEL92.1.7 cells were coated in 96 well plates and then treated with compound 2 or MK-1775 as single agents.
    After: three days of treatment, cell viability was assessed by a Cell-Titer Blue assay (Promega). The data represent the mean + S.E. (n = 5 for * 10 Compound2, n = 2 for MK-1775). IC50s were 30NM for Compound 2, € 103nM for MK-1775. See Figures 1 and 2. HEL92.1.7 cells were coated in 96-well plates and then treated with combinations of compound 2 and MK-1775 in matrix mode at the indicated concentrations.
    Three days after treatment, cell viability was assessed by a CeliTiter Blue assay.
    The reported value for each combination represents the combination index (effective reading divided by what would be expected if the compounds were additive; the expected values are the fractional effects of the single agents multiplied together, for example, if each single agent inhibited growth in 50%, then, the expected value would be 0.5 x 0.5 = 0.25). The data represent the average of two independent triplicate plate experiments were measured for each individual experiment). MK-1775 (NM) 1000 500 250 125 63 31 16 8 4 [0.90 | 0.59 [0.41 | 0.28 | 0.33 | 049 | 0.64 | 0.89 [0.99 epas 5 1.05 (& M) 75 | 075 066 | 065 | 060 | 069 | 081 | 089 | 103 | 097) 19 | 0.91 | 0.92 | 0.83 | 0.85 | 0.91 | 0.99 | 0.93 | 1.01 [1.01]
    HEL92.1.7 cells were coated in 96 well plates - in duplicate and then treated with compound 2 or MK-1775. After 2 days of treatment, one plate was analyzed by Caspase-Glo 3/7 'assay (Promega) and the other by CellTiter Blue assay.
    The reading of the Dandruff-Glo 3/7 assay was divided by the CellTiter Blue assay reading, so that the caspase activity could be normalized to an approximation of cell number.
    The graphs depicting activation of caspase 3/7 by Compound 2 and single agent treatments MK-1775 (see Figures 3 and 4). Compound 2 and MK-1775 were combined in matrix mode.
    The values represent the effective values divided by what would be expected if the compounds acted in an additive mode (the expected values are the - fractional effects of the single agents multiplied together). MK-1775 (nM) - 1000 500 250 125 63 31 16 8 to D ps Tue Ta E TE
    Example 4 Inhibition of Chk1 and inhibition of Wee1 leads to decreases in inhibitory phosphorylation of cyclin-dependent kinases HEL92 1.7 cells were treated with compound 2, MK-1775, or combinations of both (low combination = 30 nM compound 2 + 75 nM MK-1775, medium combination = 150 nM compound 2 + 375 nM MK-1775, high combination = 300 nM Compound 2 + 750 nM MK-1775) for 8 hours.
    Cell lysates were then analyzed by Western blot using antibodies specific for tyrosine phosphorylated Cdk2 15 (CDK2 pY15) and Cdc phosphorylated in threonine 14 and tyrosine 15 (Cdc2 pT14 / Y15). Band strengths were normalized to control GAPDH load.
    Values are reported normalized for vehicle control, See Figures 5 and 6 Example 5 chemicals for DNA damage and cell cycle checkpoint activation + HEL92.1.7 cells were treated with Compound 2, MK-1775, or combinations of both (low combination = 30 nM Compound 2 + 75 nM 'MK-1775, medium combination = 150 nM Compound 2 + 375 nM MK-1775, high combination = 300 nM Compound 2 + 750 nM MK-1775) for 8 hours. Cell lysates were then analyzed by Western blot using antibodies specific for serine 139 phosphorylated H2A.X (H2A.X pS139) and serine 345 phosphorylated Chk1 (Chk1 p345). Band strengths were normalized to control GAPDH load. Values are reported normalized for vehicle control. See Figures 7 and 8.
    i Example 6 Inhibition of Chki and inhibition of Wee1 lead to the collapse of replication of
    DNA HEL92.1.7 cells were treated with compound 2, MK-1775, or combinations of both for 16 hours. The cells were then analyzed by the Click-iT EdU Flow Cytometry Assay Kit (Invitrogen) according to the manufacturer's instructions. Cells with replicated DNA replication were defined as having S-phase DNA content, but negative staining for EdU. See Figure 9.
    Although the invention has been described in combination with the listed modalities, it will be understood that they are not intended to limit the invention to those modalities. On the contrary, the invention aims to cover all alternatives, modifications and equivalents, which can be included in the scope of the present invention as defined by the claims. Thus, the above description is considered to be illustrative only of the principles of the invention.
    The words "comprise", "comprising", "include", "including" and "includes" when used in this specification and in the following claims are intended to specify the presence of mentioned aspects, integers, components, or steps, but do not exclude the need for addition of 1m or more
    权利要求:
    Claims (18)
    [1]
    1. CHK1 inhibitor, characterized by the fact that it is selected from the group consisting of: (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2, 3-b] pyridin-3-ilnicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrol [2,3-b] pyridin-3- iNisobutyramide, ( R) -N- (5-bromo-4- (3- (methylamino) piperidin-1-yl) -1H-pyrrole [2,3-b] pyridin-3- iNnicotinamide, (R) -N- (4- (3-aminopiperidin-1-i1) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-i1) -5-methylnicotinamide, (R) -N- (4- (3-aminopiperidin-1 -yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-yl) cyclopropanecarboxamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H -pyrrole [2,3-b] pyridin-3-i1) -3-methylbutanamide and (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3 -b] pyridin-3-i1) -2-cyclopropylacetamide, in combination with a WEE1 inhibitor, for use in a method to treat cancer.
    [2]
    2. Pharmaceutical composition, characterized by the fact that it comprises a CHK1 inhibitor selected from the group consisting of: (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2 , 3-b] pyridin-3-iD) nicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3- iDisobutiramide, (R) -N- (5-bromo-4- (3- (methylamino) piperidin-1-yl) -1H-pyrrol [2,3-b] pyridin-3- i) nicotinamide, (R) - N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-yl) -5-methylnicotinamide, - (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrol [2,3-b] pyridin-3-yl) cyclopropanecarboxamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-i1) -3-
    methylbutanamide and (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrol [2,3-b] pyridin-3-i1) -2-cyclopropylacetamide, in combination with a pharmaceutical composition comprising a WEE1 inhibitor, for use in a method for treating a hyperproliferative disease, such as cancer.
    [3]
    3. Kit, characterized by the fact that it comprises a CHK1 inhibitor selected from the group consisting of: (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2, 3-b] pyridin-3-ilnicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrol [2,3-b] pyridin-3-iN) isobutyramide , (R) -N- (5-bromo-4- (3- (methylamino) piperidin-1-yl) -1H-pyrrole [2,3-b] pyridin-3- iNnicotinamide, (R) -N- ( 4- (3-aminopiperidin-1-i1) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-i1) -5-methylnicotinamide, (R) -N- (4- (3-aminopiperidin -1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-iNcyclopropanecarboxamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H -pyrrole [2,3-b] pyridin-3-i1) -3-methylbutanamide and (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3 -b] pyridin-3-i1) -2-cyclopropylacetamide, and a WEE1 inhibitor.
    [4]
    4. Kit, characterized by the fact that it comprises: (a) a CHK1 inhibitor selected from the group consisting of: (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H- pyrrole [2,3-b] pyridin-3- i) nicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridine -3- iNisobutyramide, (R) -N- (5-bromo-4- (3- (methylamino) piperidin-1-yl) -1H-pyrrole [2,3-b] pyridin-3- i) nicotinamide,
    (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-i1) -5- - methylnicotinamide, (R) -N - (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-iNcyclopropanecarboxamide, (R) -N- (4- (3-aminopiperidin-1- il) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-i1) -3-methylbutanamide and (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromine -1H-pyrrole [2,3-b] pyridin-3-i1) -2-cyclopropylacetamide, and (b) a WEE1 inhibitor, for use in combination in a method to treat or prevent a hyperproliferative disease, such as cancer.
    [5]
    5. Kit, characterized by the fact that it comprises: (a) a CHK1 inhibitor selected from the group consisting of: (R) -N- (4- (3-aminopiperidin-1-iI) -5-bromo-1H- pyrrole [2,3-b] pyridin-3-iDNnicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrole [2,3-b] pyridin-3 - iN) isobutyramide, (R) -N- (5-bromo-4- (3- (methylamino) piperidin-1-yl) -1H-pyrrole [2,3-b] pyridin-3-ilnicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrol [2,3-b] pyridin-3-yl) -5-methylnicotinamide, (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H-pyrrol [2,3-b] pyridin-3-yl) cyclopropanecarboxamide, (R) -N- (4- (3-aminopiperidin-1-iI) -5-bromo-1H-pyrrole [2,3-b] pyridin-3-i1) -3-methylbutanamide and (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromo-1H -pyrrole [2,3-b] pyridin-3-yl) -2-cyclopropylacetamide, (b) a WEE1 inhibitor, and (c) a DNA damaging agent, for use in combination in a method to treat or prevent a hyperproliferative disease, such as cancer.
    [6]
    6. Inhibitor, composition, or kit according to any of claims 1 to 5, characterized by the fact that the WEE1 inhibitor is MK-1775.
    [7]
    Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized in that the WEE1 inhibitor is (R) -N- (4- (3-aminopiperidin-1-yl) -5- bromo-1H-pyrrole [2,3-b] pyridin-3-i) nicotinamide.
    [8]
    8. Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized in that the WEE1 inhibitor is (R) -N- (4- (3-aminopiperidin-1-yl) -5- bromo-1H-pyrrole [2,3-b] pyridin-3-iDisobutiramide.
    [9]
    9. Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized by the fact that the WEE1 inhibitor is (R) -N- (5-bromo-4- (3- (methylamino) piperidin- 1-yl) -1H-pyrrole [2,3-b] pyridin-3-ilnicotinamide.
    [10]
    10. Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized in that the inhibitor of WEE1 (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromine -1H-pyrrole [2,3-b] pyridin-3-i1) -5-methylnicotinamide.
    [11]
    11. Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized in that the inhibitor of WEE1 (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromine -1H-pyrrole [2,3-b] pyridin-3-iNcyclopropanecarboxamide.
    [12]
    12. Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized in that the inhibitor of WEE1 (R) -N- (4- (3-aminopiperidin-1-yl) -5-bromine -1H-pyrrole [2,3-b] pyridin-3-i1) -3-methylbutanamide.
    [13]
    13. Inhibitor, composition, or kit according to any one of claims 1 to 6, characterized in that the WEE1 inhibitor is (R) -N- (4- (3-aminopiperidin-1-yl) -5- bromo-1H-pyrrole [2,3-b] pyridin-3-yl) -2-cyclopropylacetamide.
    [14]
    14. Inhibitor, composition, or kit according to any one of claims 1 to 13, characterized in that it further comprises] a harmful DNA agent.
    [15]
    15. Pharmaceutical composition, characterized by the fact that it comprises a CHK1 inhibitor in combination with a pharmaceutical composition which comprises a WEE1 inhibitor for use in a method to treat a hyperproliferative disease, such as cancer.
    [16]
    16. Composition according to claim 15, characterized by the fact that the CHK1 inhibitor is selected from the group consisting of PF-00477736, AZD7762, XL844, IC-83, CHIR-124, PD-321852, LY2603618, LY2606368e SCH 900776.
    [17]
    17. Composition according to claim 15 or 16, characterized by the fact that the WEE1 inhibitor is selected from the group consisting of MK-1775, PD-166285 and PF-00120130.
    [18]
    18. Composition according to claim 15 or 16, characterized by the fact that it further comprises a harmful DNA agent.
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    法律状态:
    2020-09-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-09-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2021-01-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-01-26| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-05-11| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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