Abstract 3409: Design and characterization of highly potent and selective CDK9 heterobifunctional degraders

Abstract

Cyclin-dependent kinase 9 (CDK9) has long been considered an attractive therapeutic target for modulating transcription in cancers of high unmet clinical need. CDK9 coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release state and is considered an important co-factor for oncogenic transcription factors that drive transcription in an addictive manner. CDK9 modulation offers an approach for attenuating transcriptional dysregulation driven by amplified or overexpressed transcription factors, such as c-MYC. However, targeting CDK9 in the clinic has proven very challenging. This stems from the often highly intolerable cytotoxic effects likely due to off-target effects. Targeted protein degradation offers a novel approach for engineering enhanced selectivity and mitigating other liabilities of the conventional inhibition-driven approach that have been applied to date. Here, we present the design and characterization of a focused library of highly selective CDK9 degrader molecules with rapid kinetics and potency (half-degrading concentration of <1nM). We carry out transcriptional and phosphoproteomics profiling to comprehensively characterize the downstream effects and cellular adaptations resulting from CDK9 degradation. We gain new insights into adaptive responses to CDK9 modulation and the biological contexts most responsive for therapeutic application. Citation Format: Mohammed A. Toure, Keisuke Motoyama, André Richters, Angela N. Koehler. Design and characterization of highly potent and selective CDK9 heterobifunctional degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3409.