Adaptive mechanisms and emerging cancer therapeutics for CDK2 inhibitors

The approvals of four CDK4/6 (cyclin-dependent kinases 4 and 6) inhibitors by the US Food and Drug Administration-palbociclib, abemaciclib, ribociclib and trilaciclib-as anticancer or supportive therapies establish the critical role of CDKs in regulating the cell cycle and cancer progression. However, the emergence of drug-resistant cancers underscores the adaptability and plasticity of this cellular pathway, highlighting the need for additional therapeutic strategies. CDK2, the key kinase activated downstream of CDK4/6, has emerged as a prominent pharmaceutical target, with numerous selective inhibitors reported in recent years. This Perspective discusses the adaptive plasticity of cell-cycle control in cancer cells and then highlights current strategies to target newly emerging CDK2 druggable pockets-including orthosteric, substrate-binding and allosteric sites-with an emphasis on chemical biology approaches, aiming to inspire the next generation of CDK2 inhibitors and kinase-targeted therapies more broadly.