Abstract 5844: Novel inhibition of transcriptional cyclin-dependent kinases, CDK12/13, using CT7439 as a treatment for colorectal cancer with CDK12 upregulation

Abstract Introduction: Cell proliferation is a hallmark of cancer growth, and regulation of transcription and translation is key to controlling proliferative capacity. A crucial connection between transcriptional regulation and the cell cycle occurs via transcriptional cyclin-dependent kinases (CDKs), CDK12 and its paralog, CDK13, which regulate transcription by phosphorylating the c-terminal domain of RNA polymerase II. Both CDK12 and CDK13 are often upregulated in solid tumors, rendering them compelling targets for therapeutic intervention. Methods: A total of eight CDK12 or CDK12/13 inhibitors with different mechanisms of action (covalent, non-covalent, proteolysis-targeting chimera, and molecular glue) were screened against a panel of cancer cell lines spanning five solid tumor types (breast, colorectal, lung, ovarian, and prostate). Colorectal cancer patient-derived organoids (PDO) were used to validate the most efficacious agents, covalent binders (THZ531 and CDK12-IN-E9). In order to determine whether CDK13 plays a compensatory role for loss of CDK12 function, knockdown of CDK13 by siRNAs was employed, followed by CDK12-specific inhibition using a proteolysis-targeting chimera (BSJ-4-116). Finally, synergy was conducted to determine whether CDK12/13 inhibition increases sensitivity to poly-ADP ribose polymerase (PARP) inhibition. qPCR quantified the presence of short and long isoforms of BRCA1 following CDK12/13 inhibition to confirm whether transcription elongation in DNA damage repair genes was prevented. Results: Covalent inhibition of CDK12/13 was the most efficacious across pan-cancer cell lines. Validation in colorectal cancer PDO showed greater inhibition by covalent inhibitors than standard of care chemotherapies for colorectal cancer (oxaliplatin, SN38, and 5-FU). CDK13 siRNA-mediated knockdown sensitized colorectal cell lines to the CDK12-specific inhibitor, BSJ-4-116, suggesting CDK13 may compensate for CDK12 loss of function. CDK12/13 inhibition led to downregulation of long isoforms of BRCA1, rendering cells susceptible to dual CDK12 and PARP inhibitors. These compelling data prompted evaluation of CT7439, a CDK12/13 inhibitor and cyclin K glue-degrader, which showed efficacy in the low nanomolar range for a panel of colorectal PDO. Conclusions: Here we highlight CDK12/13 inhibition as a compelling target for colorectal cancers and other solid tumors and show the importance of CDK13 compensation during CDK12 inhibition. These findings support further evaluation of the novel CDK12/13 inhibitor, CT7439, for the treatment of solid tumors with CDK12/13 upregulation. Citation Format: Jason A. Somarelli, Wylie Katherine Watlington, Divya Dayanidhi, Mohammad Zokaasadi, John B. Mantyh, Pelumi D. Olawuni, Gabrielle Rupprecht, Jeremy Force, Shannon McCall, Ashwani K. Bahl, David S. Hsu. Novel inhibition of transcriptional cyclin-dependent kinases, CDK12/13, using CT7439 as a treatment for colorectal cancer with CDK12 upregulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5844.