UC Berkeley

Drug discovery has changed greatly over time. Humanity once derived most medications from natural products and now we can treat a person by gene-editing their cells within their body. It is only recently that the scientific community even understands what proteins cause specific phenotypes or diseases. This work explores the challenges of modern drug discovery and the solution that is presented in the form of covalency. In addition, the relevant biology and druggability of the oncogenic transcription factor MYC is discussed. Lastly, this dissertation discusses the development and characterization of covalent stereoselective sulfinyl aziridines that act as destabilizing degraders against MYC.Chapter 1 provides an overview on drug development and the use of covalent small molecules to overcome challenges in discovery and target identification. This section discusses the nature of covalent binding and how it differs from traditional inhibitor modalities. Briefly, workflows in chemoproteomics and bio-orthogonal chemistry are highlighted.Chapter 2 focuses on the biology and efforts to drug the oncogene, MYC. Nonmalignant MYC biology and the subsequent transition to malignancy is evaluated. Similarly, the complexity of MYC cancer biology and its involvement in almost every area of cell biology. Brief discussions of previous efforts to drug MYC are included with a focus on small molecule modalities.Chapter 3 describes the discovery and characterization of covalent stereoselective sulfinyl aziridine small molecules that act upon MYC as destabilizing degraders. This work builds upon previous literature to exploit the intrinsic disorder of many transcription factors as a vulnerability for their targeted degradation. I screen a library of stereochemically paired small molecules made by Dr. Kelvin Li, evaluating for MYC degradation. Upon discovery of the hit molecule KL2-236, I characterize the mechanism of degradation through proteasomal rescue studies as well as characterize the interaction between KL2- 236 and MYC through multiple chemical biology approaches. I establish KL2-236 as a destabilizing degrader and use site directed mutagenesis to determine the site of modification of KL2-236 on MYC. I show on-target downstream effects of MYC  degradation leading to a reduction in MYC transcriptional activity and MYC target genes by transcriptomics. Dr. Kelvin Li used structure-activity relationship to synthesize over 180 analogs of KL2-236 and I tested the analogs to find a more potent and effective MYC degrader in KL4-219A. I fully characterize KL4-219A and find that it is more potent than the initial hit compound, but also selective for MYC in proteome wide analysis. Overall, this work reveals a novel ligandable site within MYC and indicates that certain intrinsically disordered regions within transcription factors, such as MYC, can be interrogated by isomerically unique chiral small molecules, leading to destabilization and degradation.