PCNA inhibitors
Described herein, inter alia, are compositions of PCNA modulators and methods for treating or preventing cancer.
1. A pharmaceutical composition comprising a compound, an anti-cancer agent, and a pharmaceutically acceptable excipient, wherein the anti-cancer agent is a platinum-based compound, topoisomerase inhibitor, EGFR inhibitor, ras inhibitor, MEK inhibitor, signal transduction inhibitor, or signal transduction modulator; and
wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof; wherein
Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl;
Ring B is substituted or unsubstituted 1-naphthyl, or substituted or unsubstituted isoquinolinyl;
R 1 is independently a halogen, —CX 13 , —CHX 12 , —CH 2 X 1 , —CN, —SO n1 R 10 , —SO v1 NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m1 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 1 3 , —OCHX 12 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is independently hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is independently hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CX A 3 , —CHX A 2 , —CH 2 X A , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
z1 is an integer from 0 to 4;
m1 and v1 are independently 1 or 2;
n1 is independently an integer from 0 to 4; and
X 1 , X 2 , X 3 , and X A are independently —Cl, —Br, —I, or —F.
2. The pharmaceutical composition of claim 1 , wherein the compound has the formula:
wherein
R 4 is independently a halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —CN, —SO n4 R 14 , —SO v4 NR 11 R 12 , —NHNH 2 , —ONR 11 R 12 , —NHC═(O)NHNH 2 , —NHC═(O)NR 11 R 12 , —N(O) m4 , —NR 11 R 12 , —C(O)R 13 , —C(O)—OR 13 , —C(O)NR 11 R 12 , —OR 14 , —NR 11 SO 2 R 14 , —NR 11 C═(O)R 13 , —NR 11 C(O)—OR 13 , —NR 11 OR 13 , —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently a halogen, —CX 5 3 , —CHX 5 2 , —CH 2 X 5 , —CN, —SO n5 R 18 , —SO v5 NR 15 R 16 , —NHNH 2 , —ONR 15 R 16 , —NHC═(O)NHNH 2 , —NHC═(O)NR 15 R 16 , —N(O) m5 , —NR 15 R 16 , —C(O)R 17 , —C(O)—OR 17 , —C(O)NR 15 R 16 , —OR 18 , —NR 15 SO 2 R 18 , —NR 15 C═(O)R 17 , —NR 15 C(O)—OR 17 , —NR 15 OR 17 , —OCX 5 3 , —OCHX 5 2 , —OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 5 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen, —CX B 3 , —CHX B 2 , —CH 2 X B , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, halogen, —CX C 3 , —CHX C 2 , —CH 2 X C , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
z2 is an integer from 0 to 5;
z3 is an integer from 0 to 7;
m4, m5, v4 and v5 are independently 1 or 2;
n4 and n5 are independently an integer from 0 to 4; and
X 4 , X 5 , X B , and X C are independently —Cl, —Br, —I, or —F.
3. The pharmaceutical composition of claim 2 , wherein R 4 is independently halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OH, —OR 14 , unsubstituted methyl, or unsubstituted methoxy.
4. The pharmaceutical composition of claim 3 , wherein R 14 is hydrogen or unsubstituted C 1 -C 3 alkyl.
5. The pharmaceutical composition of claim 2 , wherein R 5 is independently halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OH, unsubstituted methyl, or unsubstituted methoxy.
6. The pharmaceutical composition of claim 1 , wherein R 1 is independently halogen, —OH, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, unsubstituted methyl, or unsubstituted methoxy.
7. The pharmaceutical composition of claim 1 , wherein R 2 is hydrogen.
8. The pharmaceutical composition of claim 1 , wherein R 3 is hydrogen.
9. The pharmaceutical composition of claim 1 , wherein Ring A is a substituted or unsubstituted phenyl.
10. The pharmaceutical composition of claim 1 , wherein Ring B is a substituted or unsubstituted 1-napththyl.
11. The pharmaceutical composition of claim 1 , wherein Ring B is a substituted or unsubstituted 1-isoquinolinyl, or a substituted or unsubstituted 4-isoquinolinyl.
12. The pharmaceutical composition of claim 2 , wherein the compound has the formula:
13. The pharmaceutical composition of claim 1 , wherein the compound has the formula:
14. The pharmaceutical composition of claim 1 , wherein the compound has the formula:
15. The pharmaceutical composition of claim 1 , wherein the anti-cancer agent is etoposide, camptothecin, gemcitabine, gefitinib, afatinib, or erlotinib.
16. A method of treating a disease associated with PCNA activity in a patient having said disease, said method comprising administering the pharmaceutical composition of claim 1 .
17. A method of treating cancer in a patient having said cancer, said method comprising administering the pharmaceutical composition of claim 1 .
18. The method of claim 17 , wherein said cancer is a sarcoma, adenocarcinoma, leukemia, or lymphoma.
19. The method of claim 17 , wherein said cancer is a lung cancer, colon cancer, a central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, or hematoid carcinoma.
20. The method of claim 17 , further comprising administering radiation.