A newly developed compound called CM101 helps to clear toxic proteins in the brains of mice, and could be a viable avenue for the treatment of some neurodegenerative diseases, including Parkinson’s disease, researchers say.
This finding was recently presented at the annual meeting of the Society of Neuroscience, in a presentation titled, “Multi-kinase inhibition may have optimal effects on neurodegenerative pathologies via the tyrosine kinase discoidin domain receptors (DDRs).”
Many neurodegenerative diseases are characterized by the buildup of toxic proteins in the brain — for instance, alpha-synuclein in Parkinson’s disease and tau and amyloid-beta in Alzheimer’s disease.
Researchers have been looking for ways to induce neurons (brain cells) to turn on processes that help them clear unneeded proteins, which may help remove these toxic molecules. In a press release, Charbel Moussa, PhD, an associate professor of neurology at Georgetown University and senior author of the study, described this as turning on the “garbage disposal” in neurons.
Researchers had previously investigated tyrosine kinase (TK) inhibitors as a way to do this. TKs play many roles in normal cell functioning; for instance, they are critical in helping cells divide — which is why TK inhibitors, used at high doses, have been developed as treatments for some cancers.
“The idea with these frequent high doses is that controlling cell division or proliferation while keeping the garbage disposal working overtime will incinerate cells that are rapidly dividing. These cancer cells will cannibalize themselves,” said Alan Fowler, a PhD student at Georgetown and study co-investigator.
In experimenting with some of these cancer agents — namely Tasigna (nilotinib) and Bosulif (bosutinib) — the researchers determined that inhibiting the tyrosine kinases called discoidin domain receptors 1 and 2 (DDR1 and DDR2, or collectively, just DDRs) might be the best way to turn on the garbage disposal in brain cells affected by neurodegeneration.
Based on these findings, they synthesized a new compound, CM101 (also known as BK40143), which specifically inhibits DDRs. Initial experiments in mouse models of neurodegenerative diseases have lent validity to CM101 as a potential therapy for these conditions.
“This agent has undergone extensive testing in several animal models of neurodegeneration, and it represents a good candidate that should be investigated in first-in-human trials. We have so far shown that this agent has a superior efficacy to clear neurotoxic proteins in animals compared to similar agents, and we identified DDRs as a preferential and optimal drug target. The next step is to investigate drug toxicity in order to obtain regulatory permission for human application,” Moussa said.
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