9SXI

HUMAN CD38 ECTODOMAIN BOUND TO CVN14-ADPR ADDUCT

This is a non-PDB format compatible entry.

Summary for 9SXI

• Entry DOI: 10.2210/pdb9sxi/pdb
• Descriptor: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-[3-[4-methyl-6-[[4-[2,2,2-tris(fluoranyl)ethylamino]cyclohexyl]carbamoyl]pyrimidin-2-yl]imidazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate, GLYCEROL, ... (4 entities in total)
• Functional Keywords: cd38, nad+, nucleophilic, covalent inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 30693.45

Authors

Rangel, V.,Zebisch, M.,Stott, A. (deposition date: 2025-10-09, release date: 2026-02-11, Last modification date: 2026-03-04)

Primary citation

Stott, A.J.,Burli, R.W.,Doyle, K.J.,Dickson, L.,Hewer, R.C.,Pickford, P.,Roberts, M.J.,Waters-Hall, R.,Wu, Y.,Zebisch, M.,Rangel, V.,Geitmann, M.,Matthews, K.,Brice, N.L.,Carlton, M.,Dawson, L.A.,Harvey, J.R.M.
Discovery of Potent, Selective, and Brain-Penetrant Small Molecule CD38 Inhibitors.
Acs Med.Chem.Lett., 17:259-265, 2026

PubMed 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 , 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 ADPRCD38 complex, revealing an uncompetitive binding mode. provides a molecular tool to investigate CD38 biology in neurodegeneration and supports the development of next-generation brain-penetrant CD38 inhibitors.

PubMed: 41704394
DOI: 10.1021/acsmedchemlett.5c00727

Experimental method

X-RAY DIFFRACTION (1.74 Å)