Abstract
Cluster of differentiation 38 (CD38) is a nicotinamide adenine dinucleotide (NAD(+))-consuming ectoenzyme abundantly expressed in brain regions involved in motor control and cognition. Given the central role of NAD(+) in maintaining neuronal health, inhibition of CD38, resulting in NAD(+) elevation, has emerged as a potential therapeutic approach for neurodegenerative diseases and age-associated cognitive decline. Herein, we report the rational, structure-guided optimization of a series of small-molecule CD38 inhibitors, culminating in the identification of CVN14, a potent, selective, and brain-penetrant tool molecule with favorable pharmacokinetic properties for advanced preclinical evaluation. We further disclose the first high-resolution X-ray crystal structure of the CVN14-ADPR-CD38 complex, revealing an uncompetitive binding mode. CVN14 provides a molecular tool to investigate CD38 biology in neurodegeneration and supports the development of next-generation brain-penetrant CD38 inhibitors.