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.