磷酸肌醇3-激酶（PI3K）信号通路异常在癌症中最为常见，已成为癌症药物开发的重要靶点。基于4-甲基喹唑啉骨架，我们设计并合成了一系列新颖的双价PI3K抑制剂，具有不同的连接器长度和类型。双价PI3K抑制剂27相对于相应的单价抑制剂11表现出改善的PI3K活性和抗增殖细胞活性。化合物27还明显阻断了PI3K信号通路，诱导细胞周期在G1期停滞，并抑制了克隆形成和细胞迁移。此外，化合物27在HGC-27移植小鼠模型中展现了剂量依赖的抗癌效果。总体而言，本研究提供了一种可能的策略，用于发现用于癌症治疗的新型PI3K抑制剂。版权所有© 2023 Elsevier出版公司，保留所有权利。

Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer and has become a key target for cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.Copyright © 2023 Elsevier Inc. All rights reserved.