Abstract 7004: CT7439 an oral first-in class selective CDK12 and 13 inhibitor and cyclin K degrader: Profiling activity and combination efficacy in an ovarian cancer model

Abstract CT7439 is a small molecule kinase inhibitor of cyclin-dependent kinases CDK12/CDK13 that received FDA IND approval in 2023. In addition to inhibiting CDK12/13, CT7439 acts as a monovalent glue degrader of cyclin K (CCNK), the cyclin required for CDK12/13 function. Proteomics quantification by DIA LCS/LCSMS mass spectrometry was conducted after exposure to 30 nM CT7439 at 4 & 24 hr. OV-90 cells were cultured in media and exposed to CT7439 at various concentrations and time points. Combination studies were conducted with the PARP inhibitors and Carboplatin. The following parameters were assessed: proliferation/cell survival, confluency formation, CCNK protein levels and DNA damage and repair (DDR) genes. CT7439 inhibited OV-90 cell growth with an IC50 of 4.4nM and this impact on cell growth was significantly attenuated by co-treatment of the cells with proteasome inhibitor. Proteomics analysis revealed that 99 proteins were found to be differentially abundant between samples from CT7439 (30 nM) treated and vehicle at 4 hrs. At 24 hrs 1, 666 proteins were found to be differentially abundant. CCNK was the only cyclin impacted by CT7439. Pathway and ontology analysis showed reduced abundance for proteins involved in DDR. DDR genes (BRCA1, ERCC4, RAD51C and POLQ) are inhibited by treatment with CT7439, at concentrations consistent with inhibition of CDK12/13-Cyclin K in the cells. CT7439 activity in OV-90 in cellular assays: Data is mean ± SD (**Western blot, *qPCR) In addition to single agent activity of CT7439 a strong combination activity between CT7439 and the PARP inhibitors Olaparib, Niraparib and AZD10530 as well as the carboplatin was observed in an OV-90 cellular confluency assay. CT7439 is an orally bioavailable selective CDK12/13 inhibitor and degrader of CCNK. Pre-clinical studies demonstrates clinical potential for monotherapy use in solid tumors and as a combination therapy with agents known to cause a DNA damage response. Citation Format: Ashwani K. Bahl, Matthew Carr, Stuart Thompson, Adrian Campbell, Andrew Leishman, Edward Ainscow. CT7439 an oral first-in class selective CDK12 and 13 inhibitor and cyclin K degrader: Profiling activity and combination efficacy in an ovarian cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7004.