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.