Dual Nicotinamide Phosphoribosyltransferase (NAMPT) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors for the Treatment of Drug-Resistant Nonsmall-Cell Lung Cancer.

Depleting NAD by blocking its biosynthesis has emerged as an attractive anticancer strategy. Simultaneous blockade of NAD production from the salvage and synthesis pathways by targeting NAMPT and IDO1 could achieve more effective NAD reduction and, subsequently, more robust antitumor efficacy. Herein, we report the discovery of the first series of dual NAMPT and IDO1 inhibitors according to multitarget drug rationales. Compound has good and balanced inhibitory potencies against NAMPT and IDO1, and significantly inhibits both proliferation and migration of a NSCLC cell line resistant to taxol and FK866 (A549/R cells). Compound also displays potent antitumor efficacy in A549/R xenograft mouse models with no significant toxicity. Moreover, this compound enhances the susceptibility of A549/R cells to taxol and . This work provides an efficient approach to targeting NAD metabolism in the area of cancer therapy, especially in the context of drug resistance.