Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2023-05-08 , DOI: 10.1016/j.bioorg.2023.106594 Hao Lei 1 , Weiming Duan 1 , San-Qi Zhang 1 , Yifan Feng 1 , Mengyan Ma 1 , Bo Yuan 1 , Minhang Xin 1
The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and β. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.
中文翻译:
发现带有氨基酸片段的有效选择性 PI3Kδ 抑制剂
PI3Kδ的选择性抑制是治疗血液恶性肿瘤的潜在治疗策略。在此,我们报道了一系列带有氨基酸片段的化合物作为有效的选择性 PI3Kδ 抑制剂。其中,化合物A10表现出亚纳摩尔PI3Kδ效力。在细胞测定中,A10对 SU-DHL-6 细胞具有很强的抗增殖作用,引起细胞周期停滞,并诱导 SU-DHL-6 细胞凋亡。对接研究表明A10与PI3Kδ蛋白紧密结合,呈平面构象。总的来说,化合物A10代表了一种有前途的有效且选择性的 PI3Kδ 抑制剂,带有氨基酸片段,尽管对 PI3Kγ 具有中等选择性,但对 PI3Kα 和 β 具有优异的选择性。这项研究表明,使用氨基酸片段代替吡咯烷环是设计有效 PI3Kδ 抑制剂的新策略。