Andrew Stott, Roland W. Bürli, Kevin Doyle, Louise Dickson, Richard C. Hewer, Philip Pickford, Maxine J. Roberts, Rosie Waters-Hall, Yiming Wu, M. Zebisch, V.L. Rangel, Matthis Geitmann, Kim L. Matthews, Nicola Brice, Mark Carlton, Lee A. Dawson, Jenna R. M. Harvey
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.