Compositions and methods for treating cancer
Provided herein, inter alia, are compositions and methods useful for treating hyperproliferative diseases, including cancer and non-malignant hyperproliferative diseases.
1. A method of treating lung cancer or breast cancer in a patient in need of said treatment, said method comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:
wherein L 1 is a substituted or unsubstituted alkylene;
L 2 is a substituted or unsubstituted heteroalkylene, or —O—;
R 1 is hydrogen, or substituted or unsubstituted alkyl; and
R 2 is hydrogen, or substituted or unsubstituted aryl.
2. The method of claim 1 ,
wherein L 1 is a substituted or unsubstituted C 1 -C 4 alkylene;
L 2 is a substituted or unsubstituted heteroalkylene, or —O—;
R 1 is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl; and
R 2 is hydrogen, or substituted or unsubstituted aryl.
3. The method of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula:
4. The method of claim 1 , wherein L 1 is unsubstituted methylene.
5. The method of claim 1 , wherein L 1 is substituted or unsubstituted propylene.
6. The method of claim 1 , wherein L 1 is —C(R 8 ) 2 —;
R 8 is independently oxo, halogen, —CX 8 3 , —CHX 8 2 , —CH 2 X 8 , —OCX 8 3 , —OCH 2 X 8 , —OCHX 8 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —SH, —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHC(O)H, —NHC(O)OH, —NHOH, R 9 -substituted or unsubstituted alkyl, R 9 -substituted or unsubstituted heteroalkyl, R 9 -substituted or unsubstituted cycloalkyl, R 9 -substituted or unsubstituted heterocycloalkyl, R 9 -substituted or unsubstituted aryl, or R 9 -substituted or unsubstituted heteroaryl;
R 9 is independently oxo, halogen, —CX 9 3 , —CHX 9 2 , —CH 2 X 9 , —OCX 9 3 , —OCH 2 X 9 , —OCHX 9 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —SH, —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHC(O)H, —NHC(O)OH, —NHOH, R 10 -substituted or unsubstituted alkyl, R 10 -substituted or unsubstituted heteroalkyl, R 10 -substituted or unsubstituted cycloalkyl, R 10 -substituted or unsubstituted heterocycloalkyl, R 10 -substituted or unsubstituted aryl, or R 10 -substituted or unsubstituted heteroaryl;
R 10 is independently oxo, halogen, —CX 10 3 , —CHX 10 2 , —CH 2 X 10 , —OCX 10 3 , —OCH 2 X 10 , —OCHX 10 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —SH, —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHC(O)H, —NHC(O)OH, —NHOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and
X 8 , X 9 , and X 10 are independently —F, —Cl, —Br, or —I.
7. The method of claim 1 , wherein L 1 is —C(R 8 ) 2 —;
R 8 is independently oxo, halogen, —CX 8 3 , —CHX 8 2 , —CH 2 X 8 , —OCX 8 3 , —OCH 2 X 8 , —OCHX 8 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —SH, —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHC(O)H, —NHC(O)OH, —NHOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and
X 8 is independently —F, —Cl, —Br, or —I.
8. The method of claim 1 , wherein the compound is:
9. The method of claim 1 , wherein the compound is:
10. The method of claim 1 , wherein the compound is:
11. The method of claim 1 wherein the cancer is lung cancer.
12. The method of claim 1 wherein the cancer is non-small cell lung cancer.
13. The method of claim 1 wherein the cancer is breast cancer.
14. The method of claim 1 wherein the cancer is triple negative breast cancer.
15. The method of claim 1 wherein the cancer is resistant to an anti-cancer agent.
16. The method of claim 1 , further comprising administering a second agent, wherein the second agent is an anti-cancer agent.
17. The method of claim 16 , wherein the second agent is glembatumumab vedotin, capecitabine, nab-paclitaxel, sacituzumab govitecan, vantictumab, atezolizumab, gemcitabine, metformin, iniparib, irinotecan, trastuzumab, trastuzumab emtansine, anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprolide, megestrol acetate, tamoxifen, toremifene, palbociclib, everolimus, cyclophosphamide, docetaxel, doxorubicin, epirubicin, methotrexate, paclitaxel, 5-fluorouracil, capecitabine, carboplatin, cisplatin, eribulin, ixabepilone, liposomal doxorubicin, vinorelbine, pertuzumab, lapatinib, erlotinib, gefitinib, cetuximab, panitumumab, afatinib, cisplatin, carboplatin, or nedaplatin.
18. A method of decreasing the level of activity of NF-κB or mTOR in a cell comprising contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:
wherein L 1 is a substituted or unsubstituted alkylene;
L 2 is a substituted or unsubstituted heteroalkylene, or —O—;
R 1 is hydrogen, or substituted or unsubstituted alkyl; and
R 2 is hydrogen, or substituted or unsubstituted aryl.
19. A method of increasing the level of activity of TSC1 or TSC2 in a cell comprising contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:
wherein L 1 is a substituted or unsubstituted alkylene;
L 2 is a substituted or unsubstituted heteroalkylene, or —O—;
R 1 is hydrogen, or substituted or unsubstituted alkyl; and
R 2 is hydrogen, or substituted or unsubstituted aryl.