CN045 Promotes Oligodendrocyte Maturation, Modest Remyelination in Preclinical MS Study

An experimental small molecule called CN045 promoted the maturation of myelin-producing cells and demonstrated remyelination activity in preclinical models of multiple sclerosis (MS), according to a recent report and findings published in npj Drug Discovery. The compound was identified through a screen of approximately 20,000 central nervous system (CNS)-biased small molecules and subsequently demonstrated activity in both mouse and human oligodendrocyte progenitor cells (OPCs), as well as in a mouse model of chronic demyelination.^1,2

The findings provide early proof of concept for CN045 as a potential remyelination therapy, although the compound remains a preclinical lead and requires additional optimization and testing before it could advance toward human studies.

“CN045 is brain-penetrable with low [cell toxicity] … and appears to be an attractive contender that can be improved by further lead optimization to generate a clinical candidate for enhancing remyelination in MS patients,” investigators noted in a statement.¹

Identifying a Lead for Remyelination

In MS, immune-mediated damage to myelin can disrupt signaling along nerve fibers and contribute to neurologic symptoms and disability. Current disease-modifying therapies primarily target the inflammatory activity underlying the disease, while approaches designed to directly restore damaged myelin remain an area of investigation.^1,2

Because oligodendrocytes are responsible for producing myelin in the central nervous system, researchers developed a phenotypic screening strategy focused on promoting the maturation of OPCs into mature oligodendrocytes.

Senior author Bruce D. Trapp, PhD, chair of the Department of Neurosciences at the Lerner Research Institute at Cleveland Clinic in Ohio, and investigators screened approximately 20,000 small molecules selected for properties favorable to CNS drug development. The initial screen generated 390 positive hits, which were subsequently narrowed through secondary screening and dose-response testing. Eighteen compounds demonstrated half-maximal effective concentrations (EC50s) below 200 nM, with CN045 emerging as the lead candidate.²

CN045 demonstrated an EC50 of 40 nM in the OPC differentiation assay and showed greater activity than T3, which was used as a positive control. Treatment increased the proportion of mature oligodendrocytes and expression of myelin-associated proteins, including proteolipid protein and myelin basic protein.

CN045 Demonstrates Activity in Human Cells

Investigators next evaluated whether the compound's effects could be reproduced using human OPCs. Cells obtained from 3 surgically resected human brain specimens were treated with CN045 for 14 days.

Compared with vehicle, CN045 significantly increased the proportion of mature O4-positive oligodendrocytes. The treated cells also demonstrated increased myelin-like ensheathment of engineered nanofibers, with greater numbers of oligodendrocytes associated with the fibers and increased total ensheathed length.²

These findings extended the initial mouse-cell results and suggested that CN045 could promote not only OPC maturation but also characteristics associated with myelin production in human cells.

Modest Remyelination Observed in Mice

The investigators then evaluated CN045 in a cuprizone/rapamycin mouse model of chronic demyelination. Following 12 weeks of demyelination, animals received CN045 or vehicle for 6 weeks before investigators assessed remyelination.²

CN045 significantly increased remyelination in the corpus callosum, hippocampus, and cerebral cortex, encompassing both white and gray matter regions. Despite reaching statistical significance, the investigators characterized the magnitude of the remyelination effect as modest.

Researchers also noted an important limitation of the model: cuprizone/rapamycin-induced demyelination does not reproduce the primary immune-mediated demyelinating process that occurs in MS. As a result, additional disease-relevant models will be needed to determine whether the findings translate to the pathophysiology of MS.

Further Optimization Required

Additional testing identified several characteristics that could support further development of CN045, including brain penetration and low cytotoxicity in cellular and animal studies. However, pharmacokinetic analyses identified high intrinsic clearance in mouse and human hepatocytes and a short in vivo half-life, limiting the compound's current drug-like properties.²

To address these limitations, investigators have begun evaluating structural analogues of CN045. Among 20 analogues tested, several retained activity in the OPC differentiation assay, providing an early structure-activity relationship that could inform efforts to improve the compound's metabolic stability and other pharmacologic properties.

The molecular target of CN045 also remains unknown. Because the investigators used a phenotypic rather than target-based screening strategy, additional work is underway to determine the mechanism responsible for the compound's effects on OPC maturation.

Overall, the findings establish CN045 as an early lead for a potential remyelination approach in MS, but the compound remains several steps removed from clinical testing. Further lead optimization, mechanistic studies, and evaluation in additional models will be needed to determine whether CN045 or a related compound can produce sufficiently robust remyelination to warrant clinical development.

REFERENCES
1. Horak M. Experimental compound boosts myelin repair in preclinical MS study. Multiple Sclerosis. July 28, 2026. Accessed August 13, 2026.
2. Yang Y, Bai B, Knutsen LJS, et al. A novel small molecule remyelination therapy for multiple sclerosis. npj Drug Discovery. 2026;3:24. doi:10.1038/s44386-026-00060-7.