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Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy
Yue Li1, Yuanyuan Liu2,3, Yong Zhang4
1Department of Medicinal Chemistry, Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai 201112, P. R. China.
Abstract:
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.
Insights
A novel CD38 inhibitor, compound 1, effectively treats mitochondrial myopathy in mice by restoring NAD+ levels and improving muscle function. This compound shows promise for treating related human diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- CD38 is a key enzyme regulating NAD+ levels in mammals.
- Dysfunctional CD38 activity is implicated in mitochondrial disorders.
- Targeting CD38 offers a potential therapeutic strategy for metabolic diseases.
Purpose of the Study:
- To develop and evaluate a novel, potent, and selective CD38 inhibitor.
- To assess the therapeutic efficacy of compound 1 in a mouse model of mitochondrial myopathy.
- To elucidate the molecular mechanisms underlying compound 1's effects.
Main Methods:
- In vitro enzymatic assays to determine CD38 inhibition.
- In vivo studies using a Pus1 knockout mouse model of mitochondrial myopathy.
- Biochemical analysis of NAD+ levels, Nrf2 expression, and lactate production.
- RNA sequencing to analyze gene expression changes.
Main Results:
- Compound 1 demonstrated high potency (11 nM IC50) and selectivity for CD38.
- Treatment with compound 1 dose-dependently improved running endurance in mice.
- Compound 1 elevated muscle NAD+ levels, increased Nrf2 expression, and reduced lactate.
- RNA sequencing revealed compound 1's impact on mitochondrial function and muscle-related pathways.
Conclusions:
- Compound 1 is a potent and selective CD38 inhibitor with significant in vivo efficacy.
- Compound 1 effectively ameliorates mitochondrial myopathy symptoms in a preclinical model.
- The favorable pharmacokinetic and safety profile suggests compound 1's potential as a therapeutic agent.
