Rational design of NAMPT-based dual inhibitors with improved drug-like and pharmacokinetic properties for cancer treatment

While PD-1/PD-L1 immunotherapy has demonstrated significant clinical efficacy, current small-molecule inhibitors are limited by suboptimal oral bioavailability (F < 10 %) due to unfavorable physicochemical properties. To address this challenge, we developed bifunctional inhibitors that simultaneously target NAMPT (nicotinamide phosphoribosyltransferase) and PD-L1, leveraging NAMPT's critical role in immunometabolic reprogramming. The lead compound T8 exhibited potent dual-target inhibition, with an IC₅₀ of 63 nM against PD-L1 and 0.582 μM against NAMPT, along with superior pharmacokinetic properties, including oral bioavailability of 78.8 % in mice and 64.4 % in rats. In B16–F10 melanoma models, T8 achieved enhanced tumor growth inhibition (TGI = 40.1 %) compared to anti-PD-L1 antibodies (28.2 %), mechanistically attributed to the activation of the tumor immune microenvironment. This study identifies T8 as a potent orally bioavailable dual PD-L1/NAMPT inhibitor, thereby validating the co-targeting of NAMPT as a transformative strategy for cancer immunotherapy.