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

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 multiple cancer cell lines. Furthermore, 20 and 35 displayed good plasma exposure levels in mice and are suitable for in vivo efficacy studies. Lastly, compound 20 effectively suppressed tumor growth in vivo in a xenograft model without apparent toxicity.

Automated summary

In this study, we reported a potent AKT degrader MS21 and its structure-activity relationship (SAR) studies. Additionally, we discovered another VHL-recruiting AKT degrader MS143 with similar efficacy as MS21, as well as a novel CRBN-recruiting PROTAC MS5033. These compounds effectively degraded AKT by hijacking the ubiquitin-proteasome system and showed significant inhibition of cell growth in multiple cancer cell lines. Furthermore, they exhibited good plasma exposure levels in mice and were suitable for in vivo studies.