Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer

[Display omitted] •A series of 7-azaindole-based PI3K inhibitors with enhanced CDK2 inhibition were developed for the discovery of anti-TNBC drug candidates.•SAR studies identified FD2056 as a novel potent PI3K inhibitor with enhanced CDK2 inhibition.•In vitro and in vivo studies validate its anti-TNBC efficacy.•FD2056 could serve as a lead compound for the development of PI3K/CDK2 dual inhibitor. 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.