Lysine-Targeted\nCovalent\nInhibitors of PI3Kδ Synthesis and Screening by In Situ Interaction\nUpgradation

Targeting the lysine residue of protein\nkinases to develop covalent\ninhibitors is an emerging hotspot. Herein, we have reported an approach\nto develop lysine-targeted covalent inhibitors of PI3Kδ by in\nsitu interaction upgradation of the H-bonding to covalent bonding.\nSeveral warhead groups were introduced and screened in situ, leading\nto lysine-targeted covalent inhibitors bearing aromatic esters with\nhigh bioactivity and PI3Kδ selectivity. Compound <b>A11</b> bearing phenolic ester was finally optimized to show a long duration\nof action in SU-DHL-6 cells by multiple assays. Docking simulation\nand further protein mass spectrometry confirmed that <b>A11</b> bound to PI3Kδ by covalent-bonding interactions with Lys779.\nFurthermore, <b>A11</b> exhibited potently antitumor efficacy\nwithout obvious toxicity in the SU-DHL-6 and Pfeiffer xenograft mouse\nmodels. This study identified <b>A11</b> to be a much more effective\nantitumor agent in vitro and in vivo as a lysine-targeted covalent\ninhibitor, and it also provided a practical approach for the development\nof lysine-targeted covalent inhibitors.