Li Zhang

Date of Award

Fall 2021

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Campbell McInnes

Second Advisor

Igor Roninson

Abstract

CDK8 and its homolog CDK19 are essential for transcription regulation and their dysregulation has been identified in numerous diseases, especially in cancers. CDK8 and CDK19 have been implicated in cancer development through their kinase activity and kinase independent functions. Despite the existing CDK8/19 inhibitors, there is still a need to develop novel CDK8/19 inhibitors with improved potency and PK profile. It is also necessary to develop CDK8/19 degraders that are able to eliminate the kinase-independent functions. Although two CDK8-degrading PROteolysis Activating Chimeras (PROTACs) have been reported, they have limited CDK8 degradation efficacy and no effect on CDK19. PROTACs with improved degradation efficacy targeting both CDK8 and CDK19 are required.

Here we present the design, synthesis, optimization, and biological evaluation of two series of CDK8/19 inhibitors and three series of CDK8/19 degrading PROTACs. The quinoline-6-carbonitrile series is derived from CDK8/19 inhibitors Senexin A and Senexin B. Among this chemical series, Senexin C (2.20a) exhibited the best inhibitory activity, being more potent and metabolically stable than its parental inhibitor. Moreover, Senexin C (2.20a) possesses unique properties compared to other CDK8/19 inhibitors including sustained target inhibition and highly tumor-enriched pharmacokinetics (PK) profile with in vivo therapeutic efficacy, making it a promising lead CDK8/19 inhibitor. The thienopyridine series is derived from CDK8/19 inhibitors 15u and 15w that were initially identified as bone anabolic agents. Among this series, several compounds exhibited comparable inhibitory activity to the parental inhibitors but with unfavorable PK. Despite that, the achieved SAR will contribute to the future CDK8/19 inhibitor development of the thienopyridine series. The three series of PROTAC molecules were derived from 15u, Senexin C, and BI-1347 respectively. Among them, BI-1347-derived PROTAC 4.48 shows the best CDK8/19 degradation potency in different cell lines and species. Moreover, it offers a greater long-term benefit for leukemia treatment than its parental CDK8/19 inhibitor BI1347.

This dissertation provides insights regarding the development of novel CDK8/19 inhibitors and degraders as potential anti-cancer agents and should contribute to the future inhibitor and degrader development targeting CDK8/19 and other kinase targets

Rights

© 2021, Li Zhang

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