Drug design for cyclin-dependent kinase 9 (CDK9) inhibitors in silico

Despite the potential of cyclin-dependent kinase 9 (CDK9) as a novel target for various malignancies and HIV replication in infected cells, no effective inhibitors have been developed. In the preceding study, we deciphered a hidden cavity in CDK9 upon molecular dynamics (MD) simulation of the CDK9/CyclinT1/Tat trimolecular complex. This cavity is located near the CDK9 ATP pocket (continuous cavity I, CCI) and extends to the cyclin T1 (CycT1) contact surface (CCII and CCIII). In this study, we searched for compounds similar to previously identified CDK9 inhibitors using cheminformatics to identify compounds that are better suited to this hidden cavity. We identified compounds that effectively targeted CCII and CCIII of CDK9. We confirmed their inhibitory effects on the CDK9/CycT1 complex <i>in vitro</i>. As these inhibitory compounds target only a portion (CCII and CCIII cavities) of CDK9, we examined their combinatorial effects with the known CDK inhibitor <b>BS-181</b>. As expected, this combination exerted an additive inhibitory effect on CDK9 expression. These findings confirm the presence of a CDK9 hidden cavity that was revealed transiently by MD simulations, thus providing promising evidence for the development of CDK9 inhibitors.