Microtubule stabilizing drugs for neurodegenerative disease and spinal cord injury

Our 3-5 year goal is to develop small molecules drugs for neurodegenerative diseases and/or spinal cord injury that bind directly to microtubules and stabilize them in CNS neurons and glia. This well-defined pharmacological mechanism protects neurons from degenerative pathologies, and promotes axon growth in damaged spinal cord. It showed considerable promise in rodent models of neurodegeneration, spinal cord injury and schizophrenia using epothilone-D and -B as CNS-penetrating tool compounds. The potential efficacy of epothilones in man is limited by high peripheral toxicity. They kill dividing cells by stabilizing mitotic spindle microtubules and were originally developed as cytotoxic cancer drugs, making them a poor starting point for neurology drugs, despite their promising mechanism. To develop fundamentally less toxic microtubule stabilizing drugs that retain neuro-protective and neuro–regenerative activities we will adopt approaches from GPCR pharmacology that have never been applied to microtubule drugs. We will use ligand displacement assays as our primary screen, and then evaluate neuroprotective, cytotoxic and microtubule stabilizing activities in follow-up assays. In a 1-year pilot we propose to test the concept that we can obtain scaffolds which bind to the epothilone site and exhibit superior neuroprotective to cytotoxic ratios compared to current tool compounds. If we validate this concept, we will pursue a drug development project based using the assays and concepts we develop during the pilot phase.