Design and Synthesis of Purine-Based Compounds Targeting CDK11: Implications for Breast Cancer Therapy

Nada Elkholy, Pompom Ghosh, Luxin Sun, Dylan Grassie, Ernst Schonbrunn, Derek Duckett, Andrii Monastyrskyi

Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL 33612

CDK11 emerges as a pivotal regulator in the proliferation and metastasis of various cancer cell lines, notably including HER2+ and triple negative breast cancer. Despite its critical role, CDK11 remains largely understudied within the CDKs transcriptional subfamily. Pre-clinical validation studies employing siRNA and CRISPR technologies, demonstrate the profound impact of genetic knockdown of CDK11 on breast cancer cell growth, apoptosis induction, and inhibition of migration and invasion, along with significant suppression of tumor growth in vivo. Addressing the limitations of existing CDK11 inhibitors, we have employed structure-based drug design to develop a novel series of purine-based CDK11 inhibitors. Differential scanning fluorimetry confirmed preferential binding of the S-enantiomer within the series, suggesting potential kinome-wide selectivity. Furthermore, radiometric kinase assays validated inhibition of CDK11 functional activity. Subsequent biochemical and cell-based assays, including NanoBRET target engagement and CellTiter-Glo viability assays, will be conducted for compound triaging. These endeavors aim to discover potent, selective CDK11 probes, with the ultimate objective of elucidating the roles of these understudied proteins in relevant breast cancer models in vivo.