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

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 <b>A11</b> 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 <b>A11</b> bound to PI3Kδ by covalent-bonding interactions with Lys779. Furthermore, <b>A11</b> exhibited potently antitumor efficacy without obvious toxicity in the SU-DHL-6 and Pfeiffer xenograft mouse models. This study identified <b>A11</b> 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.