Lysine-Targeted Covalent Inhibitors of PI3Kδ Synthesis and Screening by In Situ Interaction Upgradation

• Published in: Journal of medicinal chemistry 2024-11, Vol.67 (22), p.20076-20099
• Main Authors: Yuan, Bo, Feng, Yifan, Ma, Mengyan, Duan, Weiming, Wu, Yujie, Liu, Jiaxin, Zhao, Hong-Yi, Yang, Zhe, Zhang, San-Qi, Xin, Minhang
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01284

Targeting the lysine residue of protein kinases to develop covalent inhibitors is an emerging hotspot. Herein, we have reported an approach to develop lysine-targeted covalent inhibitors of PI3Kδ by in situ interaction upgradation of the H-bonding to covalent bonding. Several warhead groups were introduced and screened in situ, leading to lysine-targeted covalent inhibitors bearing aromatic esters with high bioactivity and PI3Kδ selectivity. Compound A11 bearing phenolic ester was finally optimized to show a long duration of action in SU-DHL-6 cells by multiple assays. Docking simulation and further protein mass spectrometry confirmed that A11 bound to PI3Kδ by covalent-bonding interactions with Lys779. Furthermore, A11 exhibited potently antitumor efficacy without obvious toxicity in the SU-DHL-6 and Pfeiffer xenograft mouse models. This study identified A11 to be a much more effective antitumor agent in vitro and in vivo as a lysine-targeted covalent inhibitor, and it also provided a practical approach for the development of lysine-targeted covalent inhibitors.