UMIP-58 -Small molecule drug to treat central nervous system injury by promoting regeneration

Note:This molecule is currently being developed intoa candidate for clinical testing in cooperation with NINDS/NIH, with projectedentry into a Phase 1 clinical trial in 2024-2025. Problem: There are currently no approved drugs for encouraging the regrowth of damaged central nervous system (CNS) axons following injury. Treatment for individuals with CNS injury is therefore limited to acute intervention attempting to “spare” neural tissue, followed by managing the cumulative decline caused by the loss of motor, sensory, and/or cognitive functions. This creates a significant economic burden, not to mention the physiological, psychological, and social suffering endured by the patients and their families on a daily basis. Developing therapeutics to promote CNS recovery is challenged by the existence of two mechanisms that inhibit axon growth: 1) the lack of intrinsic regenerative capacity of neurons, and 2) the extrinsic inhibitory microenvironment confronting damaged axons. Effective cures must therefore treat both sources of regeneration failure in order to induce clinically meaningful axon regeneration. Technology: Our researchers developed a novel biotechnology platform that can efficiently identify drug targets from cellular models of disease. They applied this technology to identify and select two druggable targets, one that mediates extrinsic inhibition of axon growth (ROCK), and another that suppresses the intrinsic regenerative capacity of neurons. They then identified a single compound that co‐inhibits both drug targets while exhibiting better overall kinome‐selectivity than several FDA approved kinase inhibitors. Treating cultured neurons with this compound induced an enormous increase in neurite outgrowth (400% relative to controls). The team then tested this compound in multiple animal models of CNS injury, and found that it induces significant axon regeneration and functional recovery. Follow‐up medicinal chemistry and structure‐activity studies have further supported the relevance of the identified target kinases to the compound’s mechanism of action, and have generated candidate leads for clinical development. Peter Gutenberg pxg372@miami.edu 305-243-4604