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

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.