Novel small molecule inhibitors of STOML3 for treatment of diabetic neuropathy
Prof. Gary Lewin, Max Delbrück Center for Molecular Medicine; Dr Jane Reznick, Max Delbrück Center for Molecular Medicine ; Dr Marc Nazaré, Leibniz-Forschungsinstitut für Molekulare Pharmakologie; Dr Christiane Wetzel, Max Delbrück Center for Molecular Medicine ; Dr Alice Rossi, Max Delbrück Center for Molecular Medicine
Novel small molecule inhibitors of STOML3 (stomatin-like protein-3), a protein controlling the sensitivity of Piezo mechanically gated ion channels, are being developed to reverse mechanical hypersensitivity in pathophysiological conditions following nerve injury. Diabetic neuropathy as an example is a serious and common complication of type 1 and type 2 diabetes and about 20-50% of patients develop neuropathic pain. However, current therapeutics may only achieve up to 50% pain relief in only a third of patients. Since the pain generating mechanisms that result from nerve injury are quite diverse, response to drugs is likewise diverse and treatment is very challenging. Hence, there is a considerable medical need for novel drugs developed for specific patient groups to achieve effective pain relief.
Mechanosensitive ion channels like Piezo1 and Piezo2 are difficult targets to exploit for pharmacological intervention, as their gene deletion is lethal. The inhibitors described here circumvent these shortcomings by not directly affecting essential functions of Piezo proteins and rather targeting their modulator STOML3. Inhibitors of STOML3 oligomerization reversibly reduce the sensitivity of mechanically gated currents in sensory neurons, silence mechanoreceptors and show potent effects in vivo in models of neuropathic pain. Starting from first hits identified from screening assays designed to monitor STOML3 protein-protein interaction, several promising lead series are meanwhile available. An extensive medicinal chemistry program is currently ongoing to improve the series for systemic application.
Available for licensing or co-development
To be filed in Q2 2020
Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity. Nature Neuroscience (2017) 20 (2), 209-221.