Discovery of potent and selective CDK2 inhibitors with high safety and favorable bioavailability for the treatment of cancer.

Targeting cyclin-dependent kinases (CDKs) to inhibit the cell proliferation is considered as a promising strategy for the treatment of cancer, and the success of selective CDK4/6 inhibitors proves this concept. CDK2 plays an important role in the cell cycle and proliferation for the CCNE1-amplifed cancers and CDK4/6 inhibitors resistant breast cancers. Therefore, selective inhibition of CDK2 become research hotspots. In our work, we achieved a potent and selective CDK2 inhibitor 46 through virtual screening and systematic structural modification. Compound 46 could arrest cell cycle, promote apoptosis, and induce senescence-related phenotypes for CCNE1-amplifed ovarian cancer OVCAR3 cell line, and also displayed potent antitumor activity against OVCAR3 xenografts. Furthermore, 46 hold promise in overcoming resistance to CDK4/6 inhibitor. More significantly, 46 exhibited great safety properties and favorable pharmacokinetic profiles in vivo. All these results demonstrated that 46 was a potential candidate of novel anticancer drugs.