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

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.