Discovery of a Novel Miconazole Analogue as a Dual Apo-Ido1 Inhibitor and Abcb1 Modulator for Cancer Immunotherapy and Chemosensitizing.

concentrations. Molecular modelling and biochemical assays indicated apo-form preference for 1g, which suppressed Kyn production without affecting IDO1 protein levels or inducing apoptosis. In indirect co-cultured models, 1g reversed Kyn-mediated immunosuppression, significantly restoring pro-IL1B and TNF levels in LPS-induced THP-1 macrophages. Furthermore, 1g restored Jurkat T cell proliferation, aggregate formation, and PDCD1 expression independent of direct 1g exposure, confirming a Kyn-dependent mechanism. Finally, 1g inhibited ABCB1 function in a dose-dependent manner and enhanced the sensitivity of ABCB1-expressing cells to paclitaxel, demonstrating its efficacy as a multidrug resistance (MDR) reversal agent. Our findings characterised 1g as a promising low-micromolar dual inhibitor of apo-IDO1 and ABCB1 with minimal cytotoxicity. It simultaneously disrupts the immunosuppressive Kyn axis and modulates ABCB1-mediated efflux, which provides a robust pharmacological basis for further development of next-generation combinatorial therapies.