Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC₅₀ = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.

已证明抑制PI3Kδ是治疗血液恶性肿瘤的有效策略，其中PI3K / Akt信号通路活跃。在本文中，使用骨架解构策略制备了一系列带有丙烯酰胺片段的喹唑啉衍生物。初步的生物活性评估导致发现了铅化合物15c。 与BEZ235相比，化合物15c对PI3Kδ表现出优异的酶活性（IC ₅₀ = 27.5 nM），并且具有显着的抗增殖活性。由于对其他PI3K同工型的高选择性以及对PI3K / Akt途径的强效作用，可以将15c鉴定为值得进一步分析的有前途的PI3Kδ抑制剂。