Discovery of electrophilic degraders that exploit S_NAr chemistry.

ABSTRACT: Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles. In this study, we report the use of chemical moieties that enable nucleophilic aromatic substitution (S_NAr) reactions in the rational design of electrophilic protein degraders. Appending an

SUBMITTER: Zhuang Z 

PROVIDER: S-EPMC11463635 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature