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. Selectivity determinants revealed: The structure–activity relationships of a promising class of type III allosteric cyclin‐dependent kinase 2 (CDK2) inhibitors were explored. Additional biological evaluations allowed the discovery of a selective allosteric inhibitor of the L858R/T790M epidermal growth factor receptor (EGFR) double mutant. Modeling studies shed light on the pharmacophore requirements for switching the inhibitory activity from CDK2 to the double‐mutant EGFR.