DNA2 inhibitors for cancer treatment
Disclosed herein, inter alia, are compositions and methods for inhibiting DNA2.
1. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof; wherein the compound has formula (B):
wherein
X is R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5 or 6 membered heteroaryl;
R 2a is independently halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —C(CF 3 ) 2 OH, —C(CF 3 ) 3 , unsubstituted C 1 -C 8 alkyl, R 2b -substituted or unsubstituted 2-8 membered heteroalkyl, R 2b -substituted or unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, or R 2b -substituted or unsubstituted 5 or 6 membered heteroaryl; and
R 2b is independently halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 or 6 membered heteroaryl.
2. The method of claim 1 , wherein X is R 2a -substituted or unsubstituted C 1 -C 8 alkyl or R 2a -substituted or unsubstituted phenyl.
3. The method of claim 1 , wherein the cancer is breast cancer, colon cancer, prostate cancer, lung cancer, or ovarian cancer.
4. The method of claim 1 , further comprising administering to the patient a chemotherapeutic agent, radiation, or a combination thereof, to treat the cancer.
5. The method of claim 4 , wherein the chemotherapeutic agent is a PARP inhibitor or a topoisomerase inhibitor.
6. A method of
(i) sensitizing cancer cells to radiation therapy or chemotherapy;
(ii) potentiating clinical efficacy of a PARP inhibitor or a topoisomerase inhibitor;
(iii) inhibiting DNA replication;
(iv) suppressing DNA double-strand break repair end resection, recombination, or over-resection of nascent DNA in cells defective in fork protection, and restart of stalled DNA replication forks in cells; or
(v) interfering with telomere replication or repair;
wherein the method comprises administering a compound, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof; wherein the compound has formula (B):
wherein
X is R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5 or 6 membered heteroaryl;
R 2a is independently halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —C(CF 3 ) 2 OH, —C(CF 3 ) 3 , unsubstituted C 1 -C 8 alkyl, R 2b -substituted or unsubstituted 2-8 membered heteroalkyl, R 2b -substituted or unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, or R 2b -substituted or unsubstituted 5 or 6 membered heteroaryl; and
R 2b is independently halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2-8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 or 6 membered heteroaryl.
7. The method of claim 6 , wherein X is R 2a -substituted or unsubstituted C 1 -C 8 alkyl or R 2a -substituted or unsubstituted phenyl.
8. The method of claim 6 , wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.
9. The method of claim 6 , further comprising administering a chemotherapeutic agent, radiation, or a combination thereof.
10. The method of claim 6 , wherein the method is sensitizing cancer cells to radiation therapy or chemotherapy.
11. The method of claim 6 , wherein the method is inhibiting DNA replication.
12. A method of treating Fanconi anemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of a tautomer thereof; wherein the compound has formula (B):
wherein
X is R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5 or 6 membered heteroaryl;
R 2a is independently halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —C(CF 3 ) 2 OH, —C(CF 3 ) 3 , unsubstituted C 1 -C 8 alkyl, R 2b -substituted or unsubstituted 2-8 membered heteroalkyl, R 2b -substituted or unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, or R 2b -substituted or unsubstituted 5 or 6 membered heteroaryl; and
R 2b is independently halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2-8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 or 6 membered heteroaryl.
13. The method of claim 12 , wherein X is R 2a -substituted or unsubstituted C 1 -C 8 alkyl or R 2a -substituted or unsubstituted phenyl.
14. The method of claim 12 , wherein the patient has cancer.