KS79356, a novel kynureninase inhibitor, suppresses triple-negative breast cancer progression by attenuating the TNF-α/NFκB-CD44-Akt signaling axis.

Kynureninase (KYNU), a hydrolase in tryptophan metabolism, has been implicated in cancer progression. However, the therapeutic relevance of targeting KYNU-mediated inflammatory signaling in triple-negative breast cancer (TNBC) remains poorly defined High-throughput virtual screening (HTVS) of the ChemBridge library, combined with protein-ligand interaction profiling, molecular dynamics simulations (GROMACS), and binding free energy analysis (GMX_MMPBSA), was employed to identify KYNU inhibitors. In vitro assays were performed in SUM159, MDA-MB-231, and HBL-100 cell lines. KS79356 was identified as the lead compound, displaying strong binding affinity (- 7.8 kcal/mol), stable interactions (RMSD ≈ 0.075 nm), and favorable binding free energy (ΔG = - 23.93 kcal/mol). KS79356 effectively inhibited KYNU activity (IC₅₀ = 63.7 nM) and selectively suppressed proliferation of SUM159 (GI₅₀ = 233 nM) and MDA-MB-231 (GI₅₀ = 450.8 nM) cells. Mechanistically, KS79356 downregulated TNF-α-induced activation of the NFκB-CD44-Akt signaling axis, leading to reduced proliferation, invasion, and trans-endothelial migration, while inducing both early and late apoptosis in TNBC cells. By targeting KYNU and attenuating the TNF-α/NFκB/CD44-Akt signaling axis, KS79356 demonstrates strong antitumor activity in TNBC. These findings highlight the novelty of KYNU as a therapeutic target and support the development of KS79356 as a potential treatment strategy for TNBC progression and metastasis.Clinical trial registrationNot applicable.