New Brain-Penetrant CD38 Inhibitors Could Boost NAD+ to Fight Neurodegeneration
Scientists at Cerevance identified CVN14, a potent, selective CD38 inhibitor that crosses the blood-brain barrier and elevates NAD+ in neurons.
Summary
Researchers at Cerevance Limited used structure-guided drug design to develop CVN14, a small-molecule inhibitor of CD38 — an enzyme that consumes NAD+ and is highly expressed in brain regions governing motor control and cognition. By rationally optimizing a series of compounds, they achieved potent, selective inhibition with favorable brain penetration and pharmacokinetics. A first-of-its-kind high-resolution X-ray crystal structure of the CVN14-ADPR-CD38 complex revealed an uncompetitive binding mechanism. Elevating NAD+ via CD38 inhibition is increasingly recognized as a promising strategy for neurodegenerative diseases and age-related cognitive decline. CVN14 now serves as a validated tool molecule for advancing this biology in preclinical settings.
Detailed Summary
NAD+ is a critical coenzyme in cellular energy metabolism and DNA repair, and its decline with age is strongly linked to neurodegeneration and cognitive impairment. CD38, a multifunctional ectoenzyme abundantly expressed in brain regions such as the striatum and hippocampus, is one of the primary consumers of NAD+ in mammalian tissues. Inhibiting CD38 has therefore emerged as a compelling strategy to restore NAD+ levels in the aging brain, potentially slowing or reversing neurodegenerative processes.
The research team at Cerevance Limited, in collaboration with partners at WuXi Apptec, Evotec, and Beactica Therapeutics, undertook a rational, structure-guided medicinal chemistry campaign to identify brain-penetrant small-molecule CD38 inhibitors. Starting from an initial series, the team systematically optimized potency, selectivity, and drug-like properties — particularly blood-brain barrier (BBB) penetration, which is a major challenge for CNS-targeted therapeutics.
The culmination of this effort was CVN14, described as potent, selective against off-targets, and brain-penetrant with favorable pharmacokinetic properties suitable for advanced preclinical studies. The compound demonstrated the ability to inhibit CD38 enzymatic activity, which is expected to lead to measurable NAD+ elevation in brain tissue — the key downstream pharmacodynamic readout for this target class.
Critically, the authors solved the first high-resolution X-ray crystal structure of CVN14 bound to CD38 in complex with ADPR (adenosine diphosphate ribose), the enzymatic product of NAD+ hydrolysis. This structural data revealed that CVN14 binds in an uncompetitive manner — meaning it preferentially engages the enzyme-product complex rather than the free enzyme. This mechanistic insight is important for understanding how to further optimize next-generation inhibitors and for predicting in vivo efficacy.
CVN14 is positioned as a molecular tool compound to probe CD38 biology in neurodegeneration models, and the structural and pharmacological data disclosed provide a solid foundation for developing improved brain-penetrant CD38 inhibitors for potential therapeutic use in conditions such as Alzheimer's disease, Parkinson's disease, and age-associated cognitive decline.
Key Findings
- CVN14 is a potent, selective, brain-penetrant CD38 inhibitor with favorable preclinical pharmacokinetics.
- First high-resolution X-ray crystal structure of a CVN14-ADPR-CD38 complex was determined.
- CVN14 binds CD38 via an uncompetitive mechanism, engaging the enzyme-product complex.
- CD38 inhibition is expected to elevate NAD+ in the brain, relevant to neurodegeneration.
- Structure-guided optimization enabled a series of small molecules with CNS drug-like properties.
Methodology
The team used rational, structure-guided medicinal chemistry to optimize a series of CD38 inhibitors for potency, selectivity, and CNS penetration. X-ray crystallography was used to solve the CVN14-ADPR-CD38 complex structure at high resolution. Pharmacokinetic profiling confirmed brain penetrance and favorable ADME properties in preclinical models.
Study Limitations
CVN14 is currently a tool molecule and has not been tested in clinical or advanced in vivo disease models. The full paper's detailed potency and selectivity data are not available in the abstract alone, limiting quantitative assessment. Uncompetitive inhibitors can have complex in vivo pharmacodynamics that may complicate dose-response predictions.
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