Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer.

ID: ALA5096234

Journal: J Med Chem

Title: Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer.

Authors: Chen W, Ji M, Cheng H, Zheng M, Xia F, Min W, Yang H, Wang X, Wang L, Cao L, Yuan K, Yang P.

Abstract: Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD₅₀ > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.

CiteXplore: 36350721

DOI: 10.1021/acs.jmedchem.2c00947

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