Researchers at the University of Pittsburgh have developed GV-58, a first-in-class, use-dependent calcium channel agonist, as a potential therapeutic for Lambert-Eaton Myasthenic Syndrome (LEMS). LEMS is a neurological autoimmune disorder characterized by a reduction of presynaptic calcium channels, leading to progressive muscle weakness. GV-58 selectively targets the calcium channels that control neurotransmitter release, enhancing calcium ion flux and improving muscle function. This novel compound offers a promising treatment option for LEMS, with significantly reduced off-target effects compared to the parent molecule, (R)-roscovitine.
Description
GV-58 was developed by modifying the structure of (R)-roscovitine, a known cyclin-dependent kinase (cdk) inhibitor. The synthetic strategy involved N-9 alkylation of 2,6-dichloropurine, followed by selective substitution at the C-6 and C-2 positions to introduce various side chains. GV-58 increases the mean open time of calcium channels only after they open, making it a use-dependent agonist. This voltage-dependent action is critical for its therapeutic potential, especially when used synergistically with the potassium channel blocker 3,4-diaminopyridine (DAP).
Applications
• Therapeutic option for Lambert-Eaton Myasthenic Syndrome (LEMS)
• Potential to treat a variety of disorders that result in neuromuscular weakness
Advantages
Potential to treat the muscle weakness associated with LEMS. Approximately 20-fold less potent cyclin-dependent kinase antagonist effect compared to (R)-roscovitine. Approximately 4-fold higher efficacy as a calcium channel agonist
Invention Readiness
GV-58 has been synthesized and characterized in vitro, demonstrating significant improvements in calcium channel agonist activity and reduced cdk2 inhibition. In vivo studies in murine models are ongoing to evaluate its therapeutic potential and safety profile.
IP Status
https://patents.google.com/patent/US10752629B2Related Publication(s)
Tarr, T. B., Malick, W., Liang, M., Valdomir, G., Frasso, M., Lacomis, D., Reddel, S. W., Garcia-Ocano, A., Wipf, P., & Meriney, S. D. (2013). Evaluation of a Novel Calcium Channel Agonist for Therapeutic Potential in Lambert-Eaton Myasthenic Syndrome. Journal of Neuroscience, 33(25), 10559–10567. https://doi.org/10.1523/jneurosci.4629-12.2013
Tarr, T. B., Valdomir, G., Liang, M., Wipf, P., & Meriney, S. D. (2012). New calcium channel agonists as potential therapeutics in Lambert–Eaton myasthenic syndrome and other neuromuscular diseases. Annals of the New York Academy of Sciences, 1275(1), 85–91. https://doi.org/10.1111/nyas.12001
