Use of atr inhibitors in combination with parp inhibitors for treating cancer

A method of treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of an ATR inhibitor and a therapeutically effective amount of a PARP inhibitor, wherein the cancer has a loss of function of ATM, BRCA2, RNAse H2A, RNAse H2B, CDK12, or a combination thereof, or wherein the cancer is an ALT+ cancer;

• and wherein the PARP inhibitor is a compound of formula (III) or (IV):
• wherein
• X1 and X2 are each independently selected from N and C(H),
• X3 is independently selected from N and C(R4), wherein R4 is H or fluoro,
• R1 is C1-4 alkyl or C1-4 fluoroalkyl,
• R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl, and
• R3 is H or C1-4 alkyl,
• or a pharmaceutically acceptable salt thereof
• provided that:
• when X1 is N, then X2 is C(H), and X3 is C(R4),
• when X2 is N, then X1 is C(H), and X3 is C(R4), and
• when X3 is N, then X1 and X2 are both C(H);
• or
• wherein
• R1 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C1-4 fluoroalkyl, and C1-4 alkyloxy;
• R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl;
• R3 is H or C1-4 alkyl;
• and
• R4 is halo or C1-4 alkyl,
• or a pharmaceutically acceptable salt thereof.

A method of treating a cancer in a subject, the method comprising:

• (i) identifying the cancer as having a loss of function of ATM, BRCA2, RNAse H2A, RNAse H2B, CDK12, or a combination thereof, or as an ALT+ cancer;
• and
• (ii) administering to the subject in need thereof a therapeutically effective amount of an ATR inhibitor and a therapeutically effective amount of a PARP inhibitor of formula (III) or (IV):
• wherein
• X1 and X2 are each independently selected from N and C(H),
• X3 is independently selected from N and C(R4), wherein R4 is H or fluoro,
• R1 is C1-4 alkyl or C1-4 fluoroalkyl,
• R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl, and
• R3 is H or C1-4 alkyl,
• or a pharmaceutically acceptable salt thereof
• provided that:
• when X1 is N, then X2 is C(H), and X3 is C(R4),
• when X2 is N, then X1 is C(H), and X3 is C(R4), and
• when X3 is N, then X1 and X2 are both C(H);
• or
• wherein
• R1 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C1-4 fluoroalkyl, and C1-4 alkyloxy;
• R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl;
• R3 is H or C1-4 alkyl;
• and
• R4 is halo or C1-4 alkyl,
• or a pharmaceutically acceptable salt thereof.

A method of inducing cell death in an aberrant cancer cell having a loss of function of ATM, BRCA2, RNAse H2A, RNAse H2B, CDK12, or a combination thereof, or in an ALT+ cancer cell, the method comprising contacting the cell with an effective amount of an ATR inhibitor and an effective amount of a PARP inhibitor, the effective amounts being sufficient to induce cell death in the aberrant cancer cell;

• and wherein the PARP inhibitor is a compound of formula (III) or (IV):
• wherein
• X1 and X2 are each independently selected from N and C(H),
• X3 is independently selected from N and C(R4), wherein R4 is H or fluoro,
• R1 is C1-4 alkyl or C1-4 fluoroalkyl,
• R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl, and
• R3 is H or C1-4 alkyl,
• or a pharmaceutically acceptable salt thereof
• provided that:
• when X1 is N, then X2 is C(H), and X3 is C(R4),
• when X2 is N, then X1 is C(H), and X3 is C(R4), and
• when X3 is N, then X1 and X2 are both C(H);
• or
• wherein
• R1 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C1-4 fluoroalkyl, and C1-4 alkyloxy;
• R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl;
• R3 is H or C1-4 alkyl;
• and
• R4 is halo or C1-4 alkyl,
• or a pharmaceutically acceptable salt thereof.