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

## TL;DR

Researchers designed new inhibitors for CDK9, a potential target for HIV and cancer, by targeting a hidden cavity revealed through simulations.

## Contribution

Novel compounds targeting a hidden CDK9 cavity were identified and shown to synergize with existing inhibitors.

## Key findings

- Compounds targeting CCII and CCIII of CDK9 were identified and validated in vitro.
- Combining these compounds with BS-181 showed additive inhibitory effects on CDK9.
- The hidden cavity in CDK9 was confirmed to be a viable target for drug development.

## Abstract

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 in vitro. As these inhibitory compounds target only a portion (CCII and CCIII cavities) of CDK9, we examined their combinatorial effects with the known CDK inhibitor BS-181. 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.

•CDK9 is a feasible target for HIV, but no effective inhibitors have been developed.•We previously reported a hidden cavity linking the ATP- and cyclin T1-binding sites of CDK9.•We found novel compounds targeting this hidden cavity.•These compounds inhibited CDK9 and exhibited more than additive effects with BS-181.•Discovering compounds for this cavity opens new potential for better CDK9 inhibitors.

CDK9 is a feasible target for HIV, but no effective inhibitors have been developed.

We previously reported a hidden cavity linking the ATP- and cyclin T1-binding sites of CDK9.

We found novel compounds targeting this hidden cavity.

These compounds inhibited CDK9 and exhibited more than additive effects with BS-181.

Discovering compounds for this cavity opens new potential for better CDK9 inhibitors.