CDK inhibitors under clinical evaluation Biology Diagrams The purine core has been extensively explored in the development of kinase inhibitors. 156 Trisubstituted purines were one of the first CDK inhibitors to be developed as cancer therapeutics. 157โ159 2 is a CDK inhibitor that targets CDKs 1, 2, 4, 5, and 9. Rationales for and against CDK Inhibitors as Anticancer Therapeutics. An early indicator that curing cancer may not be achieved by inhibiting CDKs was the observation that the proliferation of some cancer cell lines was not blocked by inactivating CDK2 function using a variety of methods (Tetsu and McCormick, 2003). Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR +) metastatic breast cancer, but their effectiveness remains limited in other cancer types.CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the
CDK inhibitors developed in the early stage lack efficacy and selectivity in clinical practice, and the therapeutic effect is limited. Pan-CDK inhibitors have displayed remarkable anti-tumor efficacy. However, due to their low specificity and severe side effects, pan-CDK inhibitors have not been approved for clinical (cancer) treatment.
selective inhibitor puts the brakes on cancer cells Biology Diagrams
Classification of CDK Inhibitors. CDK inhibitors are categorized by their mechanism of action and binding characteristics. These classifications distinguish ATP-competitive inhibitors from those that modulate kinase activity through alternative mechanisms, each offering different levels of selectivity, potency, and therapeutic applicability.
A major principle of precision oncology is the development of molecular target-selective inhibitors that allow for a higher therapeutic index and full inhibition of the drug target without dose-limiting toxicities, thereby inducing deeper and more prolonged clinical responses. 1 Such agents would be predicted to have better safety profiles and thus enable safer therapeutic combinations. Development of CDK4/6 inhibitors. The next phase of CDK inhibitor development focused on selectivity for targeting CDK4/6. Palbociclib (Table 1), the first CDK inhibitor to gain FDA approval 40
dependent kinases as cancer therapeutics Biology Diagrams
An attractive feature of PROTACS is that poorly selective CDK inhibitors may be transformed into selective degraders based on the external lysine map on the targeted CDK. 88, 89, The development of CDK8 inhibitors as potential cancer therapeutic agents is a controversial topic in the recent literature. 2 Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RP, United Kingdom; Cancer Research UK Cancer Therapeutics Unit, hurdle in the clinic for most protein kinase inhibitors and resistance mechanism are beginning to be identified for CDK inhibitors. This suggests that the selective inhibitors may be best used
