Identification and optimization of a novel phosphoinositide 3-kinaseγ (PI3Kγ) inhibitor as a potential anticancer agent against breast cancer

The PI3K/Akt/mTOR signaling pathway serves as a key regulator in controlling cell growth, metabolism, and survival, and its abnormal activation is strongly implicated in tumorigenesis and poor prognosis of various malignancies, including breast cancer. Given its prominence in breast cancer pathogenesis, this pathway represents a compelling target for therapeutic intervention. In the present study, a virtual ligand screening approach was employed to identify novel PI3Kγ inhibitors, leading to the selection of six potential compounds (L1–L6), with L6 showing the highest binding affinity and stability in the PI3Kγ active site. Molecular docking analysis revealed that L6 interacts with key amino acid residues, notably Glu-880, similarly to other known flavonoid inhibitors, suggesting a conserved binding mechanism. Subsequent biological evaluation showed that L6 significantly inhibited proliferation of MCF7 breast cancer cells with an IC₅₀ of 3.9 µM. Mechanistic studies indicated that L6 induces cell cycle arrest at the G2/M phase by downregulating CDK1 and Cyclin B1 and promotes apoptosis via activation of caspase-3. Furthermore, L6 suppressed the expression of pro-metastatic genes S100A4 and MMP-9, further supporting its anticancer potential. The pharmacokinetic analysis also revealed favourable ADMET properties for L6, suggesting good drug-likeness and safety. These findings highlight L6 as a promising PI3Kγ inhibitor with structural and functional advantages. Its antiproliferative, pro-apoptotic, and gene-suppressive effects support its potential in breast cancer therapy and warrant further development as a next-generation anticancer agent.