Jia Wenqing, Cheng Xianchao
School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250200, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Biology (Basel). 2025 Jul 21;14(7):896. doi: 10.3390/biology14070896.
Phosphatidylinositol 3-kinase alpha (PI3Kα) is frequently mutated in head and neck squamous cell carcinoma (HNSCC), leading to the constitutive activation of the PI3K/Akt pathway, which promotes tumor cell proliferation, survival, and metastasis. PI3Kα allosteric inhibitors demonstrate therapeutic potential as both monotherapy and combination therapy, particularly in patients with mutations or resistance to immunotherapy, through the precise targeting of mutant PI3Kα. Compared to ATP-competitive PI3Kα inhibitors such as Alpelisib, the allosteric inhibitor exhibits enhanced selectivity for mutant PI3Kα while minimizing the inhibition of wild-type PI3Kα, thereby reducing side effects such as hyperglycemia. To date, no allosteric PI3Kα inhibitors have been approved for clinical use. To develop novel PI3Kα inhibitors with improved safety and efficacy, we employed a scaffold hopping approach to structurally modify and constructed a compound library. Based on the structural information of the PI3Kα allosteric site, we conducted the systematic virtual screening of 11,550 molecules from databases to identify lead compounds. Through integrated approaches, including molecular docking studies, target validation, druggability evaluation, molecular dynamics simulations, and metabolic pathway and metabolite analyses, we successfully identified a promising novel allosteric PI3Kα inhibitor, (3-(2-chloro-5-fluorophenyl)isoindolin-1-one). has not been previously reported as a PI3Kα inhibitor, and provides an excellent foundation for subsequent lead optimization, offering a significant starting point for the development of more potent PI3Kα allosteric inhibitors.
磷脂酰肌醇3-激酶α（PI3Kα）在头颈部鳞状细胞癌（HNSCC）中经常发生突变，导致PI3K/Akt信号通路的组成性激活，进而促进肿瘤细胞的增殖、存活和转移。PI3Kα变构抑制剂作为单一疗法和联合疗法均显示出治疗潜力，特别是对于那些对免疫疗法有突变或耐药的患者，通过精确靶向突变型PI3Kα发挥作用。与ATP竞争性PI3Kα抑制剂如阿培利司相比，变构抑制剂对突变型PI3Kα表现出更高的选择性，同时将对野生型PI3Kα的抑制降至最低，从而减少高血糖等副作用。迄今为止，尚无变构PI3Kα抑制剂被批准用于临床。为了开发具有更高安全性和疗效的新型PI3Kα抑制剂，我们采用了骨架跃迁方法对其进行结构修饰并构建了一个化合物库。基于PI3Kα变构位点的结构信息，我们对数据库中的11550个分子进行了系统的虚拟筛选，以识别先导化合物。通过分子对接研究、靶点验证、成药潜力评估、分子动力学模拟以及代谢途径和代谢物分析等综合方法，我们成功鉴定出一种有前景的新型变构PI3Kα抑制剂，即（3-(2-氯-5-氟苯基)异吲哚啉-1-酮）。该化合物此前尚未作为PI3Kα抑制剂被报道，为后续的先导化合物优化提供了良好基础，为开发更有效的PI3Kα变构抑制剂提供了重要起点。
