Structure-Activity Relationships of Hexahydrocyclopenta[c]quinoline Derivatives as Allosteric Inhibitors of CDK2 and EGFR

Following the discovery of a type III allosteric modulator of cyclin-dependent kinase 2 (CDK2) characterized by a hexahydrocyclopenta[c]quinolone scaffold, three different series of its derivatives were synthesized and biologically evaluated. Docking of the synthesized compounds into the allosteric pocket of CDK2 allowed the elucidation of structure-activity relationships (SARs). Moreover, the compounds were tested on the wild-type epidermal growth factor receptor (EGFR) kinase domain (KD) and its clinically relevant T790M/L858R mutant form. Herein we describe the first SAR investigation of allosteric ligands that bind to the type III inhibitor pocket of CDK2 and EGFR-KD. Although the activity of the synthesized inhibitors needs to be improved, the obtained results provide clear-cut indications about pharmacophore requirements and selectivity determinants. Remarkably, this study led to the identification of a selective T790M/L858R EGFR allosteric inhibitor that is inactive toward both wild-type EGFR and CDK2. Finally, docking into the T790M/L858R EGFR-KD led us to hypothesize that the compounds bind to the double-mutant EGFR-KD by adopting a binding mode different from that in CDK2, thus rationalizing the observed selectivity profile.