Allosteric Modulators of CDK4 for Lung Cancer Therapeutics

Abstract

Lung cancer is the leading cause of cancer‐related death worldwide. CDK4/Cyclin D kinase is a key cell cycle regulator and constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS‐mutant lung cancer. Although several ATP‐competitive inhibitors targeting protein kinases have been developed as anticancer therapeutics, including several recently FDA‐approved CDK4 inhibitors, these compounds suffer from limited efficacy, selectivity and toxicity due to their conventional mechanism of action. Alternative strategies to overcome limitations associated with conventional kinase inhibitors include targeting protein/protein interactions and conformational transitions which are essential for kinase activation.Using a CDK4‐specific conformational biosensor that discriminates against ATP‐pocket binding compounds and that we implemented to screen a small chemical compound library of original small molecule scaffolds, we identified and validated a druggable and patentable compound that tampers with CDK4 function. This compound inhibits Rb phosphorylation, blocks proliferation of several cancer cell lines, and does not bind the ATP pocket of CDK4 nor any of 456 other kinases. An ongoing hit‐optimization process led us to identify derivatives exhibiting greater anti‐proliferative activity than Abemaciclib or Palbociclib in the A549, KRAS‐mutated NSCLC cell line. Interestingly, these non‐ATP CDK4 inhibitors only have a cytostatic effect, and do not induce cytotoxicity even at high doses. Further studies aimed at characterizing the mechanism of action of this compound have highlighted an unexpected and atypical mechanism of inhibition targeting CDK4. Our compounds constitute attractive leads as next generation of CDK4‐specific inhibitors and lung cancer therapeutics.Support or Funding InformationThis work was supported by the SATT Connectus, Strasbourg France and awarded the 2019 Best Academic Project of MATWIN (https://matwin.fr/en/cdk4ppi‐awarded‐2019‐best‐academic‐project‐by‐the‐matwin‐international‐board/)