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 <b>20</b>) with similar potency as MS21, and a novel cereblon (CRBN)-recruiting PROTAC, MS5033 (compound <b>35</b>). Compounds <b>20</b> and <b>35</b> induced rapid and robust AKT degradation in a concentration- and time-dependent manner via hijacking the ubiquitin-proteasome system. Compound <b>20</b> suppressed cell growth more effectively than AZD5363 in multiple cancer cell lines. Furthermore, <b>20</b> and <b>35</b> displayed good plasma exposure levels in mice and are suitable for in vivo efficacy studies. Lastly, compound <b>20</b> effectively suppressed tumor growth in vivo in a xenograft model without apparent toxicity.