阻断PI3K通路被认为是一种有希望的癌症治疗策略。在此，我们报道了一种利用7-氮杂吲哚基片段导向增长的新型PI3K抑制剂的发现。其中，化合物FD2056在108个激酶中表现出中等的选择性，对PI3K和CDK2具有强效的抑制活性，显示出最有前景的候选物。在细胞实验中，抑制剂FD2056显示出优于参考化合物的TNBC细胞抗增殖特性，并以剂量依赖的方式显著增加了MDA-MB-231细胞的凋亡。此外，FD2056在MDA-MB-231移植瘤模型中以15 mg/kg的口服剂量显示出比相应药物BKM120和CYC202更有效的抗TNBC活性，抑制瘤体生长了43%，且无明显毒副作用。所有这些结果表明，FD2056作为一种有前景的抗癌化合物具有进一步开发的潜力，并且共同靶向PI3K和CDK2通路可能为TNBC的治疗提供了一种替代性治疗策略。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.Copyright © 2023 Elsevier Inc. All rights reserved.