Platinum compounds, compositions, and uses thereof
The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum (IV) complex having at least one reacting group for reacting with a functional group on a protein, engineered protein, antibody, antibody fragment, peptide, agonist, antagonist, aptamer or ligand which may be capable of recognizing a selected target cell population, and/or derivatives/analogs/mimics thereof.
1. A method of inhibiting growth of a tumor comprising contacting the tumor with an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are independently selected from NH, alkyl and aryl;
R 1 and R 2 each is Cl, or R 1 and R 2 are joined to form an oxalate;
R 3 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally is substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, wherein each of the carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl,
R 4 and R 5 are each H or together constitute a cyclohexyl ring,
Z is alternatively absent, alkyl, aryl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally is substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, or alkylidene hydrazine wherein each of the carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl or alkylidene hydrazine is optionally substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl,
R 6 is a suitable reacting group for reacting with a functional group on a protein, engineered protein, antibody, antibody fragment, peptide, agonist, antagonist, aptamer or ligand which may be capable of recognizing a selected target cell population, and/or derivatives/analogs/mimics thereof, and wherein R 6 is selected from an activated disulfide group, a vinylcarbonyl group, a vinyl acetylene group, an aziridine group, an acetylene group or any of the following groups:
where R 7 is Cl, Br, F, mesylate, tosylate, O-(4-nitrophenyl), O-pentafluorophenyl, and wherein optionally the activated disulfide group, the vinylcarbonyl group, the vinyl acetylene group, the aziridine group, the acetylene group may be substituted.
2. The method of claim 1 , wherein the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, colon cancer, ovarian cancer, pancreatic cancer, bladder cancer, prostate cancer, cervical cancer, renal cancer, leukemia, central nervous system cancers, myeloma, melanoma, mesothelioma, stomach cancer, rectal cancer, cancer of the large intestine, cancer of the small intestine, esophageal cancer, uterine cancer, head and neck cancer, endometrial cancer, eye cancer, thyroid cancer, testicular cancer, bile duct cancer, liver cancer, kidney cancer, pituitary cancer, lymphoma, brain cancer, glioma, glioblastoma multiforme, meningioma, medulloblastoma, astrocytoma, neuroblastoma, basal cell carcinoma of the skin, sarcoma, synovial sarcoma, rhabdomyosarcoma, leiomyosarcoma, chondrosarcoma, and fibrosarcoma.
3. The method of claim 2 , wherein the lung cancer is a small cell lung cancer, non-small cell lung cancer, or squamous cell lung cancer.
4. The method of claim 2 , wherein the tumor is selected from non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer or colorectal cancer.
5. The method of claim 1 , wherein the tumor has KRAS mutant cells.
6. The method of claim 5 , wherein the KRAS mutant cells have at least one homozygous KRAS mutation.
7. The method of claim 1 , wherein the tumor volume is reduced.
8. The method of claim 1 , wherein the percent tumor growth inhibition (TGI %) is at least 40%, 50%, 60%, 70%, 80%, or 90%.
9. The method of claim 1 , wherein the platinum level in the tumor delivered by the compound is at least 0.50 mM/mmole/kg platinum dosed.
10. The method of claim 1 , wherein the conjugation between R 6 and the functional group takes place in vivo.
11. The method of claim 1 , wherein the conjugation between R 6 and the functional group is performed prior to administration in vivo.
12. The method of claim 1 , wherein the protein is albumin.
13. The method of claim 1 , wherein R6 is a maleimide group and the compound has Formula II:
14. The method of claim 13 , wherein the compound has Formula IIa:
15. The method of claim 13 , wherein the compound has Formula IIb:
16. The method of claim 13 , wherein R 1 and R 2 each is Cl.
17. The method of claim 13 , wherein R 1 and R 2 are joined to form an oxalate.
18. The method of claim 13 , wherein R 3 is alkyl.
19. The method of claim 18 , wherein R 3 is methyl or ethyl.
20. The method of claim 1 , wherein the compound is selected from the group consisting of: