Discovery of Potent, Selective, and Brain-Penetrant Small Molecule CD38 Inhibitors

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Cluster of differentiation 38 (CD38) is an NAD+-consuming enzyme crucial for neuronal health.
• Elevating NAD+ levels via CD38 inhibition is a promising strategy for neurodegenerative diseases and cognitive decline.

Purpose of the Study:

• To rationally design and optimize small-molecule CD38 inhibitors.
• To identify a potent, selective, and brain-penetrant inhibitor for preclinical evaluation.
• To elucidate the binding mechanism of CD38 inhibitors.

Main Methods:

• Structure-guided drug design and optimization.
• Biochemical assays for enzyme inhibition.
• Pharmacokinetic profiling.
• X-ray crystallography to determine complex structure.

Main Results:

• Identification of CVN14, a potent and selective CD38 inhibitor with favorable brain penetration and pharmacokinetics.
• Determination of the first high-resolution crystal structure of a CD38 inhibitor complex (CVN14-ADPR-CD38).
• Revealed an uncompetitive binding mode for CVN14.

Conclusions:

• CVN14 serves as a valuable molecular tool for studying CD38 in neurodegeneration.
• The findings support the development of next-generation brain-penetrant CD38 inhibitors for neurological disorders.