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

  • ACS Med Chem Lett. 2026 Jan 29;17(2):259-265. doi: 10.1021/acsmedchemlett.5c00727.
Andrew J Stott  1 ,  Roland W Bürli  1 ,  Kevin J Doyle  1 ,  Louise Dickson  1 ,  Richard C Hewer  1 ,  Philip Pickford  1 ,  Maxine J Roberts  1 ,  Rosie Waters-Hall  1 ,  Yiming Wu  2 ,  Matthias Zebisch  3 ,  Victor Rangel  3 ,  Matthis Geitmann  4 ,  Kim Matthews  1 ,  Nicola L Brice  1 ,  Mark Carlton  1 ,  Lee A Dawson  1 ,  Jenna R M Harvey  1
Affiliations
  • 1. Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.
  • 2. WuXi Apptec Co., Ltd., 288 Fute Zhong Rd., Waigaoqiao, Shanghai 200131, P. R. China.
  • 3. Evotec (U.K.) Ltd., 95 Park Drive Milton Park, Abingdon OX14 4RY, U.K.
  • 4. Beactica Therapeutics AB, Virdings allé, SE-754 50 Uppsala, Sweden.
PMID: 41704394 DOI: 10.1021/acsmedchemlett.5c00727
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.

Keywords
CD38; NAD+; neurodegeneration; small molecule inhibitor.
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