PI3Kδ抑制剂在治疗白血病、淋巴瘤和自身免疫性疾病方面扮演重要角色。本研究以我们报道的化合物为先导化合物，基于喹唑啉和吡啶并[3,2-d]嘧啶骨架设计合成了一系列含硒的PI3Kδ抑制剂。其中，Se15化合物对PI3Kδ表现出亚纳摩尔级别的抑制和强烈的δ选择性。此外，Se15化合物对SU-DHL-6细胞显示出强效的抗增殖作用，IC50值为0.16μM。分子对接研究显示，Se15能够与PI3Kδ形成多个氢键，并与PI3Kδ选择区域处于靠近并堆积的状态。综上所述，具备吡啶并[3,2-d]嘧啶骨架的富硒化合物Se15是一种新型的高效且具有选择性的PI3Kδ抑制剂。引入硒元素可以丰富PI3Kδ抑制剂的结构，并为设计新型PI3Kδ抑制剂提供了新思路。

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 μM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.Copyright © 2023 Elsevier Inc. All rights reserved.