Chemoproteomic target-class drug discovery against the deubiquitinating enzymes
Access StatusFull text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.
Chan, Wai Cheung
MetadataShow full item record
CitationChan, Wai Cheung. 2021. Chemoproteomic target-class drug discovery against the deubiquitinating enzymes. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.
AbstractModern small molecule drug discovery is dominated, and subsequently limited by a paradigm of reversible non-covalent inhibitors. The deubiquitinating enzymes (DUBs) is a class of ~100 proteases that regulate normal and pathophysiological processes through cleaving ubiquitin marks from protein substrates and is underserved by this existing paradigm. Despite intense interest, a lack of selective inhibitors and design principles impede biological investigation. Here, we develop a DUB target-class inhibitor discovery platform consisting of a tailored covalent small molecule library, mass spectrometry chemoproteomics, and a suite of orthogonal validation assays. We first demonstrate small-scale proof-of-concept and subsequent improvements (chapter 2), then apply the platform for a screening campaign to identify and validate novel DUB covalent ligands (chapter 3). This has led to a revision of statistical approaches for handling chemoproteomic screening data (chapter 4). Our systematic interrogation provides a methodological roadmap for future target-class campaigns, guiding principles for DUB-targeting medicinal chemistry, attractive chemical starting points for diverse DUBs and a first-in-class probe for studying the understudied DUB VCPIP1.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371107
- FAS Theses and Dissertations