An inhibitor of atr kinase for use in a method of treating a hyper-proliferative disease

Abstract

The present invention covers 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyra-zol-5-yl)-1,7-naphthyridine (in the following called “Compound A”), an inhibitor of ATR kinase, for use in a method of treating a hyper-proliferative disease in a subject. Preferably the hyper-proliferative disease or the subject is characterized by one or more biomarker(s) selected from a) one or more functional mutation(s) in one or more gene(s)/protein(s) selected from APC, ATG5, ARID1A, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRAF, BRCA1, BRCA2, BRIP1, CCND1, CCNE1, CCNE2, CDC7, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, DYRK1A, EGFR, ERBB2, ERBB3, ERCC2, ERCC3, ERCC4, ER-CC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, HDAC2, H2AFX, HRAS, KRAS, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, MYC, NBN, NRAS, PALB2, PARP1, PARP2, PARP3, PARP4, PCNA, PIK3CA, PMS2, POLA1, POLB, POLH, POLL, POLN, POLQ, PRKDC, PTEN, RAD9A, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TM-PRSS2, TMPRSS2-ERG, TOPBP1, TOP2A, TOP2B, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XR-CC1 XRCC2, XRCC3, XRCC4 and/or XRCC6 gene/protein; and/or b) the activation of the ALT pathway; and/or c) microsatellite instability. The present invention also covers a kit comprising Compound A together with means to detect one or more of the afore-biomarker(s) and a method for identifying a subject having a hyper-proliferative disease disposed to respond favorably to Compound A, wherein the method comprises the detection of one or more of the aforementioned biomarker(s). Further, the invention covers a method of determining whether a subject having a hyper-proliferative disease will respond to the treatment with Compound A, wherein the method comprises the detection of one or more of the aforementioned biomarker(s) in a sample of the subject.

1 . A method of treating a hyper-proliferative disease in a subject, comprising administering a therapeutically effective amount of an inhibitor of ATR kinase to the subject, wherein said subject or the hyper-proliferative disease is characterized by one or more biomarker(s) selected from the group consisting of:
 a) one or more functional mutation(s) in one or more gene(s)/protein(s) selected from the group consisting of BRCA1, APC, ATG5, ARID1A, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRAF, BRCA2, BRIP1, CCND1, CCNE1, CCNE2, CDC7, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, DYRK1A, EGFR, ERBB2, ERBB3, ERCC2, ERCC3, ERCC4, ERCC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, HDAC2, H2AFX, HRAS, KRAS, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, MYC, NBN, NRAS, PALB2, PARP1, PARP2, PARP3, PARP4, PCNA, PIK3CA, PMS2, POLA1, POLB, POLH, POLL, POLN, POLQ, PRKDC, PTEN, RAD9A, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TMPRSS2, TMPRSS2-ERG, TOPBP1, TOP2A, TOP2B, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC6 gene/protein;   b) the activation of the ALT pathway; and   c) microsatellite instability.   
     
     
         2 . The method of  claim 1 , wherein the inhibitor of ATR kinase is 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the subject or the hyper-proliferative disease is characterized by one or more biomarker(s), which comprise(s) one or more deleterious mutation(s) in one or more gene(s)/protein(s) selected from the group consisting of BRCA1, APC, ARID1A, ATG5, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, ERCC2, ERCC3, ERCC4, ERCC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, H2AFX, HDAC2, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, NBN, PALB2, PARP1, PARP2, PARP3, PARP4, PMS2, POLA1, POLB, POLH, POLN, POLN, POLQ, PRKDC, PTEN, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RAD9A, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC6. 
     
     
         4 . The method of  claim 1 , wherein the subject or the hyper-proliferative disease is characterized by one or more biomarker(s), which comprise(s) one or more deleterious mutation(s) in one or more gene(s)/protein(s) selected from the group consisting of BRCA1, ATM, BLM, BRCA2, ERCC5, FEN1, FANCD2, FANCG, H2AFX, PARP1, PCNA, POLL, POLB/POLL, RAD9A, RAD17, RAD52, REV3L, TDP2, TP53BP1, UBE2N, and XPA. 
     
     
         5 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is (are) selected from the group consisting of BRCA1, ATM, BLM, ERCC5, FEN1, FANCD2, H2AFX, PARP1, PCNA, RAD9A, RAD17, REV3L, TP53BP1, and UBE2N. 
     
     
         6 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is (are) selected from the group consisting of BRCA1, ATM, FANCD2, H2AFX, RAD17, and UBE2N. 
     
     
         7 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is (are) selected from the group consisting of BRCA1, ATM, FEN1, H2AFX, and PCNA. 
     
     
         8 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is BRCA1. 
     
     
         9 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is ATM. 
     
     
         10 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is FANCD2. 
     
     
         11 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is H2AFX. 
     
     
         12 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is RAD17. 
     
     
         13 . The method of  claim 4 , wherein the one or more gene(s)/protein(s) is UBE2N. 
     
     
         14 . The method of  claim 1 , further comprising:
 a) determining if one or more of the biomarker(s) as defined in  claim 1  are present in a sample of the subject;   b) administering a therapeutically effective amount of the inhibitor of ATR kinase, to the subject, if one or more of the biomarker(s) determined by step (a) is (are) determined positively.   
     
     
         15 . The method of  claim 14 , wherein the sample of the subject is an in vitro sample. 
     
     
         16 . (canceled) 
     
     
         17 . A kit comprising 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt together with means to detect one or more of the biomarker(s) defined in selected from the group consisting of:
 a) one or more functional mutation(s) in one or more gene(s)/protein(s) selected from the group consisting of BRCA1, APC, ATG5, ARID1A, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRAF, BRCA2, BRIP1, CCND1, CCNE1, CCNE2, CDC7, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, DYRK1A, EGFR, ERBB2, ERBB3, ERCC2, ERCC3, ERCC4, ERCC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, HDAC2, H2AFX, HRAS, KRAS, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, MYC, NBN, NRAS, PALB2, PARP1, PARP2, PARP3, PARP4, PCNA, PIK3CA, PMS2, POLA1, POLB, POLH, POLL, POLN, POLQ, PRKDC, PTEN, RAD9A, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TMPRSS2, TMPRSS2-ERG, TOPBP1, TOP2A, TOP2B, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC6 gene/protein;   b) the activation of the ALT pathway; and   c) microsatellite instability.   
     
     
         18 . A method for identifying a subject having a hyper-proliferative disease disposed to respond favorably to an inhibitor of ATR kinase wherein the method comprises the detection of one or more of the biomarker(s) selected from the group consisting of:
 a) one or more functional mutation(s) in one or more gene(s)/protein(s) selected from the group consisting of BRCA1, APC, ATG5, ARID1A, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRAF, BRCA2, BRIP1, CCND1, CCNE1, CCNE2, CDC7, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, DYRK1A, EGFR, ERBB2, ERBB3, ERCC2, ERCC3, ERCC4, ERCC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, HDAC2, H2AFX, HRAS, KRAS, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, MYC, NBN, NRAS, PALB2, PARP1, PARP2, PARP3, PARP4, PCNA, PIK3CA, PMS2, POLA1, POLB, POLH, POLL, POLN, POLQ, PRKDC, PTEN, RAD9A, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TMPRSS2, TMPRSS2-ERG, TOPBP1, TOP2A, TOP2B, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC6 gene/protein;   b) the activation of the ALT pathway; and   c) microsatellite instability,   
       in a sample of the subject. 
     
     
         19 . A method of determining whether a subject having a hyper-proliferative disease will respond to the treatment with an inhibitor of ATR kinase, wherein the method comprises the detection of one or more of the biomarker(s) selected from the group consisting of:
 a) one or more functional mutation(s) in one or more gene(s)/protein(s) selected from the group consisting of BRCA1, APC, ATG5, ARID1A, ATM, ATR, ATRIP, ATRX, BAP1, BARD1, BLM, BRAF, BRCA2, BRIP1, CCND1, CCNE1, CCNE2, CDC7, CDK12, CHEK1, CHEK2, DCLRE1A, DCLRE1B, DCLRE1C, DYRK1A, EGFR, ERBB2, ERBB3, ERCC2, ERCC3, ERCC4, ERCC5, FAM175A, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FBXO18, FBXW7, FEN1, GEN1, HDAC2, H2AFX, HRAS, KRAS, LIG4, MDC1, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH6, MYC, NBN, NRAS, PALB2, PARP1, PARP2, PARP3, PARP4, PCNA, PIK3CA, PMS2, POLA1, POLB, POLH, POLL, POLN, POLQ, PRKDC, PTEN, RAD9A, RAD17, RAD18, RAD50, RAD51, RAD52, RAD54B, RAD54L, RB1, REV3L, RPA1, RPA2, SLX4, TDP1, TDP2, TMPRSS2, TMPRSS2-ERG, TOPBP1, TOP2A, TOP2B, TP53, TP53BP1, TRRAP, UBE2N, UIMC1, USP1, WDR48, WRN, XPA, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC6 gene/protein;   b) the activation of the ALT pathway; and   c) microsatellite instability,   
       in a sample of the subject. 
     
     
         20 . The method of  claim 14 , wherein the inhibitor of ATR kinase is 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine or a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.