Date of Award

Fall 10-1-2021

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Crews, Craig


Technologies that hijack cellular pathways using bifunctional small molecules have recently risen to the forefront of the drug discovery world. The first targeted protein degradation (TPD) technology to be developed, PROteolysis Targeting Chimeras (PROTACs), were disclosed two decades ago. The recent successes of AR and ER-degrading PROTACs in pioneering clinical trials has propelled interest in developing novel platforms to further expand the druggable proteome and the arsenal of strategies that are available for therapeutic intervention. This thesis is focused on the development of novel bifunctional molecules that enable interrogation of diseases driven by traditionally challenging protein targets. The first chapter begins with a review of the important discoveries that built the foundation for modern PROTAC campaigns. I then discuss other novel bifunctional molecule technologies that have been recently developed. In chapter two I describe our development of potent DcpS targeting PROTACs. DcpS is a driver of SMA and AML, and efforts toward therapeutic intervention have been largely unsuccessful. In chapter three I describe HER3 targeting molecules. HER3 is a challenging drug target, and I will outline our dutiful efforts towards developing novel degraders to investigate HER3 driven disease. In chapter 4 I disclose PROTACs targeting Brachyury, a transcription factor that untreatable chordomas are addicted to. In chapter 5 I present efforts towards developing a novel class of bifunctional molecules that enable interrogation of disease states driven by aberrant phosphorylation. Finally, in chapter 6 I present asynthetic project where we developed a novel method for generating isoquinolones.