Preclinical pharmacokinetics and pharmacodynamics of KB-0742, a selective, oral CDK9 inhibitor

Tumorigenesis is driven by the accumulation of adverse genetic changes resulting in dysregulated transcription promoting altered gene expression and the cancer cell state. Thus, tumors can develop dependencies on the transcriptional regulators that promote the reprogrammed gene expression landscape. One such regulator is cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation and promotes activation of transcription factors. We developed a potent, selective, and orally bioavailable CDK9 inhibitor, KB-0742. KB-0742 is highly selective for CDK9 as compared to other CDKs and has shown minimal off-target effects in kinase and receptor panel screens. Here we present the nonclinical pharmacologic characterization of KB-0742. The pharmacokinetics (PK) of KB-0742 in rats and dogs showed rapid absorption and high bioavailability with a %F of ≥84 after oral administration in rats and >100 in dogs. KB-0742 exhibited low turnover in human microsome and hepatocyte preparations and is projected to have low clearance and a high volume of distribution in humans based on allometric scaling from nonclinical species. These properties may facilitate achievement of sustained target engagement in patients using intermittent dosing which may mitigate the toxicity of CDK9 inhibition. To test this hypothesis, mice bearing MV4-11 (acute myeloid leukemia) xenografts were treated with KB-0742 at either 60 mg/kg for 3-days on/4-days off or continuous dosing at 25 mg/kg. Intermittent dosing showed similar tumor growth inhibition (81%) as seen with continuous dosing (74%). Target engagement was assessed in the tumors by measuring the inhibition of RNA polymerase II (pSER2). KB-0742 treatment resulted in an over 50% decrease in pSER2 compared with vehicle-treated controls. To support the phase I clinical trial, 2 pharmacodynamic assays were developed to measure drug target engagement in peripheral blood mononuclear cells (PBMCs). The first used RNA-expression profiling to measure alterations in gene expression with treatment, and the second used MSD protein analysis to measure changes in pSER2 levels. Ex vivo experiments using PBMCs from 3 healthy donors showed an over 80% reduction in pSER2 levels at 4 hours post-exposure to 1 µM of KB-0742. Similar results were observed using the RNA-expression profiling assay, in which decreased gene expression was observed in key genes at 1 µM exposures. KB-0742’s high specificity, oral bioavailability, and favorable PK properties distinguish it from other available CDK9 inhibitors. We are currently testing the hypothesis in the clinic with a phase I trial (NCT04718675) that the ability to dose intermittently will allow for favorable anti-tumor activity while minimizing adverse effects. Citation Format: Melinda A. L. Day, Douglas C. Saffran, Nathalie Rioux, Tom Chen, Christina Lee, David B. Freeman, Crystal MacKenzie, Joseph P. Vacca, Peter B. Rahl, Benjamin Wesley Trotter, Charles Y. Lin, Pavan Kumar, Jorge DiMartino. Preclinical pharmacokinetics and pharmacodynamics of KB-0742, a selective, oral CDK9 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P228.