期刊
FUTURE MEDICINAL CHEMISTRY
卷 9, 期 13, 页码 1495-1506出版社
FUTURE SCI LTD
DOI: 10.4155/fmc-2017-0076
关键词
cancer; CDK4/6; cell cycle; drug development; drug-resistance; melanoma; MV4-11; retinoblastoma; targeted therapy
资金
- Channel 7 Children's Research Foundation [151010]
- Australian Government
Aim: Inhibitors of CDK4/6 have emerged as a powerful class of therapeutics for treatment of several malignancies. We herein describe the identification of a new series of molecules that demonstrated excellent selectivity for CDK4/6 over CDKs1, 7 and 9. Results: Medicinal chemistry optimization led to the discovery of 58 and 69 that inhibited CDK4 and CDK4/6, respectively, with high potency and selectivity, and 58 and 69 exhibited potent antiproliferative activities in a panel of human cancer cell lines including leukemia, and cancers of the breast, colon, ovary, pancreas and prostate. Conclusion: Compounds 58 and 69 caused remarkable growth inhibition of melanoma cells, particularly the cells harboring multiple BRAF and NRAS mutations, via a CDK4/6-targeted mechanism of action. [GRAPHICS] .
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