Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy

CD38 is a crucial NADase in mammalian tissues that degrades NAD⁺ and thus regulates cellular NAD⁺ levels. Abnormal CD38 expression is linked to mitochondrial dysfunction under several pathological conditions. We present a novel CD38 inhibitor, compound 1, with high potency for CD38 (IC₅₀ of 11 nM) and minimal activity against other targets. In a Pus1 knockout (Pus1^-/-) mouse model of mitochondrial myopathy, compound 1 treatment rescued the decline in running endurance in a dose-dependent manner, associated with an elevated NAD⁺ level in muscle tissue, increased expression of Nrf2, which is known to promote mitochondrial biogenesis, and reduced lactate production. RNA sequencing data indicated that compound 1 has a great effect on mitochondrial function, metabolic processes, muscle contraction/development, and actin filament organization via regulating the expression of relevant genes. Compound 1 is a promising candidate for its excellent in vivo efficacy, favorable pharmacokinetics, and attractive safety profile.