Developing CDK11 Inhibition as a Novel Anti-Cancer Strategy

Drug Discovery Award (2022-Present)

Jason Sheltzer PhD, Yale University; Jane Endicott, PhD, Newcastle University

Jason Sheltzer, PhD

Jane Endicott, PhD

Cyclin-dependent kinases (CDKs) make up an enzyme family with critical roles in cell-cycle regulation, transcriptional elongation, and additional diverse aspects of eukaryotic biology. Importantly, kinases in this class are validated targets in oncology. The CDK4/CDK6 inhibitors Abemaciclib, Palbociclib, and Ribociclib have received FDA approval for use in hormone receptor-positive breast cancer, and drugs targeting CDK2, CDK7, and CDK9 are currently undergoing clinical trials in a variety of malignancies. Despite these successes, many of the cyclin-dependent kinases are functionally uncharacterized. Moreover, most enzymes in this class lack well-characterized small molecule inhibitors that do not cross-react broadly against others in the group, making targeted drug discovery challenging. Developing such tools would be valuable in elucidating the role of these enzymes and assessing their potential as drug targets.

Jason Sheltzer’s group recently discovered that the compound OTS964, which was originally described as an inhibitor of the kinase PBK, also selectively inhibits CDK11, a poorly characterized member of the CDK family, over other CDKs. Using OTS964, the group has shed light on CDK11 biology and investigated the cancer-dependency of the enzyme. Excitingly, they have verified previous reports demonstrating that CDK11 function is required to support the proliferation of multiple cancer types, including triple-negative breast cancer and melanoma. The group will now expand their work to further validate CDK11 as a target for clinical translation and design molecules with more favorable pharmacologic properties than OTS964. To do so, they will utilize structural methods to rationally design more potent and selective CDK11 inhibitors and explore whether the therapeutic window for CDK11 inhibitor treatment can be extended using a combination treatment strategy. This project will greatly expand our understanding of CDK11 biology and will provide a crucial foundation for future medicinal chemistry work directed at generating a first-in-class CDK11 inhibitor for patient testing.