Lysine-Targeted Covalent Strategy Leading to the Discovery of Novel Potent PROTAC-Based PI3Kδ Degraders

Abstract

Proteolysis-targeting chimera (PROTAC) technology was employed to achieve the degradation of PI3Kδ in this study, and a series of PROTAC-based PI3Kδ degraders were first developed. Lysine-targeted covalent strategy led to the discovery of novel potent PROTAC-based PI3Kδ degraders. After screening and structure–activity relationship study, B14 was optimal and exhibited strong antiproliferation and selective PI3Kδ inhibition, with a high degradation value (DC₅₀ = 3.98 nM). B14 induced cell cycle arrest in the premitotic phase and prompted cell apoptosis. B14 displayed effective suppression of the tumor growth in the xenograft model and significantly promoted the PI3Kδ degradation in vivo. Most importantly, B14 bound to the Lys779 of PI3Kδ to selectively degrade PI3Kδ by covalent-bonding. Mechanistic studies indicated that the ubiquitin-proteasome pathway was involved in the degradation process. This study provided an effective approach for developing PROTAC-based PI3Kδ degraders, and the lysine-targeted covalent strategy laid the foundation for the further design of potent PI3Kδ-targeting PROTACs.