Mutant IDH1/NAMPT-IN-1 (Compound 23h) is a dual inhibitor of mutant isocitrate dehydrogenase 1 (mutantIDH1) with an IC50 of 14.93 nM, and nicotinamide phosphoribosyltransferase (NAMPT) with an IC50 of 12.56 nM. This compound can induce apoptosis and effectively crosses the blood-brain barrier.

IDH1:14.93 nM

Mutant IDH1/NAMPT-IN-1 effectively reduces 2-HG levels in U87 MG-IDH1 R132H cells in a dose-dependent manner within a concentration range of 0.5-2 μM over 48 hours. Its antiproliferative activity against U87 MG cells is demonstrated with IC 50 values of 1.26 μM (24 h), 0.77 μM (48 h), and 0.42 μM (72 h), and against U87 MG-IDH1 R132H it shows IC 50 values of 0.89 μM (24 h), 0.47 μM (48 h), and 0.32 μM (72 h). Moreover, at 0.5 μM for 6 hours, Mutant IDH1/NAMPT-IN-1 enhances the thermal stability of NAMPT and IDH1R132H in U87 MG-IDH1 R132H cells. It also induces apoptosis in these cells in a dose-dependent manner at concentrations of 0.1-2 μM over 48 hours.

Mutant IDH1/NAMPT-IN-1, administered intravenously at 10-40 mg/kg twice daily for 35 days, effectively inhibits tumor growth in BALB/c nude mice in a dose-dependent manner. At a single dose of 400 mg/kg, Mutant IDH1/NAMPT-IN-1 is safe for use in ICR mice.