Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.

ABSTRACT: IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or kinase domains of the enzyme have limited utility and targeted degradation would address additional scaffolding functions of the protein. Here, we describe the design and development of IRE1α proteolysis targeting chimeras (PROTACs) based on a lysine-reactive salicylaldehyde RNase inhibitor, and present the structure-activity relationships (SARs) that delivered the first highly selective degraders of a native ER-membrane associated protein. Medicinal chemistry optimization exploited ternary complex computational modelling to inform design, HiBiT-SpyTag IRE1α degradation and NanoBRET cereblon

SUBMITTER: Zerfas BL 

PROVIDER: S-EPMC11938282 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature