OL differentiation and axon myelination in response to numerous compounds: (A) The extent of OL differentiation was assessed within the presence of 10 nM of K101, K102, and K110, alongside identified remyelinating compounds, together with ERB-041 (10 nM), clemastine (500 nM), bazedoxifene (500 nM), LY500307 (30 nM), and E2 (50 nM) (Ai-ii). Whereas the entire variety of cells remained unaffected by therapy, a big improve in MBP + OLs was noticed with K102 and K110 in comparison with the car management (Aiii). (B) The potential of those compounds to advertise axon myelination was evaluated in co-cultures of main cortical neurons and OPCs. Dissociated cortical neurons have been maintained for 10 days earlier than the addition of shaken OPCs, which have been co-cultured in proliferative OPC + neuronal media for 3 days. The medium was then switched to OL differentiation media mixed with neuronal media for 5 days, supplemented with both car management, 10 nM of K101, K102, and K110, or identified remyelinating compounds, together with ERB-041 (10 nM), Clemastine (500 nM), Bazedoxifene (500 nM), LY500307 (30 nM), and E2 (50 nM) (Bi-ii). Neuronal cell our bodies and axons have been labeled utilizing a β3-tubulin antibody, whereas mature myelinating and non-myelinating OLs have been recognized as MBP + cells with a extremely branched morphology. A major improve in OL processes wrapping axons was noticed in cultures handled with K102, K110, Clemastine, and Bazedoxifene (Biii). Determine 1Aii and 1Bii created in BioRender. Feri, M. (2025). Credit score: Scientific Stories (2025). DOI: 10.1038/s41598-025-20254-9
A number of sclerosis (MS) is a power autoimmune illness affecting greater than 2.9 million folks worldwide. It happens when the immune system mistakenly assaults the myelin sheath, the protecting insulation round nerve fibers, inflicting disruption of nerve indicators between the mind and physique. Signs can embody numbness, tingling, imaginative and prescient loss, and paralysis.
Whereas present remedies can scale back irritation, no therapies but exist to guard neurons or restore the broken myelin sheath. Researchers have now taken a serious step ahead within the growth of such a remedy. They’ve recognized two compounds that might remyelinate broken axons.
Printed within the journal Scientific Stories, the analysis was led by Seema Tiwari-Woodruff, a professor of biomedical sciences on the College of California, Riverside, College of Drugs, and John Katzenellenbogen, a professor of chemistry on the College of Illinois Urbana-Champaign.
“Our work represents more than a decade of collaboration, with the last four years focused on identifying and optimizing new drug candidates that show strong potential to treat MS and possibly other neurological diseases involving demyelination,” Tiwari-Woodruff stated.
The researchers have been in a position to launch a program that was licensed by Cadenza Bio, Inc. The corporate is now advancing towards medical analysis as a possible first-in-class remedy for folks dwelling with MS.
From discovery to growth
The challenge builds on earlier analysis involving a compound referred to as indazole chloride, identified for selling remyelination and modulating the immune system in mouse fashions of MS. Whereas efficient, indazole chloride lacked the pharmacological properties and patentability wanted for medical growth and industrial funding, Tiwari-Woodruff stated.
In collaboration with UIUC chemists Katzenellenbogen and Sung Hoon Kim, who synthesized the compounds, Tiwari-Woodruff’s analysis group, led by current UCR graduate Micah Feri, screened greater than 60 indazole chloride analogs. This collaboration recognized two lead candidates, K102 and K110, which exhibited improved security, efficacy, and drug-like properties in each mouse fashions and human cells.
Of the 2, K102 emerged because the lead compound. The researchers discovered it not solely promotes remyelination but in addition modulates immune operate, an essential stability for MS therapies. It additionally confirmed promising leads to human oligodendrocytes, the myelinating cells of the central nervous system, derived from induced pluripotent stem cells, suggesting the potential for translatability between the animal fashions and human illness.
Underneath regular circumstances, oligodendrocyte precursor cells mature into myelin-producing oligodendrocytes to restore broken myelin. In MS, nevertheless, this pure restore course of usually fails, resulting in everlasting nerve injury. Profitable remyelination via a compound like K102 may restore quicker nerve conduction and will assist scale back long-term incapacity related to the illness.
“K110 is also a strong candidate,” Tiwari-Woodruff stated. “It has slightly different central nervous system effects and may be better suited for other conditions like spinal cord injury or traumatic brain injury, so we’re keeping it in the pipeline.”
Greater than a decade within the making
Tiwari-Woodruff and Katzenellenbogen have labored collectively for greater than 12 years. Although the preliminary focus is MS, the crew believes K102 and K110 may finally be utilized to different illnesses involving neuronal injury, together with stroke and neurodegeneration.
Cadenza Bio is now advancing K102 via the mandatory non-clinical research required to assist first-in-human medical trials.
“We’re hopeful that clinical trials can begin soon,” stated Tiwari-Woodruff. “It’s been a long journey—but this is what translational science is all about: turning discovery into real-world impact.”
Extra data:
Chloroindazole based mostly estrogen receptor β ligands with favorable pharmacokinetics promote useful remyelination and visible restoration, Scientific Stories (2025). DOI: 10.1038/s41598-025-20254-9
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