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 , with high potency for CD38 (IC of 11 nM) and minimal activity against other targets. In a Pus1 knockout (Pus1) mouse model of mitochondrial myopathy, compound 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 has a great effect on mitochondrial function, metabolic processes, muscle contraction/development, and actin filament organization via regulating the expression of relevant genes. Compound is a promising candidate for its excellent efficacy, favorable pharmacokinetics, and attractive safety profile.
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