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.

中文翻译：

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通过原位相互作用升级合成和筛选的 PI3Kδ 的赖氨酸靶向共价抑制剂


靶向蛋白激酶的赖氨酸残基以开发共价抑制剂是一个新兴的热点。在此，我们报道了一种通过将 H 键原位相互作用升级为共价键来开发 PI3Kδ 赖氨酸靶向共价抑制剂的方法。引入几个弹头组并在原位筛选，导致赖氨酸靶向共价抑制剂携带具有高生物活性和 PI3Kδ 选择性的芳香酯。最终优化了带有酚酯的化合物 A11，通过多次测定在 SU-DHL-6 细胞中显示出较长的作用持续时间。对接模拟和进一步的蛋白质质谱证实，A11 通过与 Lys779 的共价键相互作用与 PI3Kδ 结合。此外，A11 在 SU-DHL-6 和 Pfeiffer 异种移植小鼠模型中表现出有效的抗肿瘤功效，无明显毒性。本研究确定 A11 作为赖氨酸靶向共价抑制剂，在体外和体内是一种更有效的抗肿瘤药物，也为赖氨酸靶向共价抑制剂的开发提供了一种实用的方法。