Discovery of Potent, Selective, and In Vivo Efficacious AKT Kinase Protein Degraders via Structure-Activity Relationship Studies.

ABSTRACT: We recently reported a potent, selective, and in vivo efficacious AKT degrader, MS21, which is a von Hippel-Lindau (VHL)-recruiting proteolysis targeting chimera (PROTAC) based on the AKT inhibitor AZD5363. However, no structure-activity relationship (SAR) studies that resulted in this discovery have been reported. Herein, we present our SAR studies that led to the discovery of MS21, another VHL-recruiting AKT degrader, MS143 (compound 20) with similar potency as MS21, and a novel cereblon (CRBN)-recruiting PROTAC, MS5033 (compound 35). Compounds 20 and 35 induced rapid and robust AKT degradation in a concentration- and time-dependent manner via hijacking the ubiquitin-proteasome system. Compound 20 suppressed cell growth more effectively than AZD5363 in

SUBMITTER: Yu X 

PROVIDER: S-EPMC8900464 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature