Identification of a Small Molecule as Potential Hypoxia-Selective Agents by Reducing Membrane Localization of ENO1 in...

The hypoxic microenvironment of pancreatic cancer drives tumorigenesis, invasion, multidrug resistance, and poor prognosis. Rakicidin A exhibits hypoxia-selective cytotoxicity, while its stability, structure-activity relationship (SAR), and molecular target remain unclear. Here, we developed an efficient synthetic route to generate a library of 34 rakicidin A analogues. SAR analysis identified compound 10e as the most potent derivative. Target identification revealed that 10e covalently bound to Cys357 of enolase 1 (ENO1). Mechanistically, 10e disrupted ENO1 membrane translocation and its interaction with c-MET, leading to suppression of the PI3K/AKT signaling pathway. In vivo studies demonstrated that 10e significantly inhibited tumor growth in pancreatic cancer xenograft models. This work identifies 10e as a novel hypoxia-selective rakicidin analogue targeting ENO1 and highlights inhibition of ENO1 membrane localization as a promising strategy for hypoxia-directed pancreatic cancer therapy.