2. Academic Validation
  3. Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy

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

  • J Med Chem. 2023 Sep 28;66(18):12762-12775. doi: 10.1021/acs.jmedchem.3c00391.
Yue Li 1,  Yuanyuan Liu 2 3,  Yong Zhang 4,  Yong Wu 1,  Zili Xing 2,  JianFei Wang 5 6,  Guo-Huang Fan 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai 201112, P. R. China.
  • 2 Department of Neurosciences, Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai 201112, P. R. China.
  • 3 Guangxi Key Laboratory of Regenerative Medicine, and Guangxi Key Laboratory of Brain Science, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning 530021, Guangxi , China.
  • 4 Department of Integrated Biological Platform Sciences, Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai 201112, P. R. China.
  • 5 Executive Office, Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai 201112, P. R. China.
  • 6 Shanghai Laboratory Animal Research Center, Shanghai 200031, China.
PMID: 37696000 DOI: 10.1021/acs.jmedchem.3c00391
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.

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