Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and the only approved treatment extends life by just a few months on average. The vast majority of patients with ALS exhibit abnormal deposits of misfolded and aggregated TAR DNA binding protein 43 (TDP43) in their brain and spinal cord. These observations suggest that ALS is characterized by a mismatch between the production and clearance of misfolded proteins, similar to other neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Autophagy is one of the two major protein clearance pathways in cells and the only pathway thought to be capable of clearing accumulated toxic misfolded proteins. We hypothesized that stimulating the endogenous autophagy pathway in brain cells could be a therapeutic strategy for treating ALS and other disorders characterized by protein misfolding and accumulation. We conducted a candidate screen and identified small molecules that induce autophagy in neurons. Using computational chemistry and the initial structure-activity relationships, we developed a pharmacophore and performed <i>in silico</i> screening of a 1M compound library and identified additional small-molecule autophagy inducers that were more potent and had a wider therapeutic window. One of the major challenges of developing autophagy inducers is that many of the conventional assays are slow and insensitive, relying on snap-shot measures of autophagy pathway intermediates to infer flux through the pathway. To overcome this limitation, we developed a new optical pulse-labeling method to directly measure flux through the autophagy pathway, and we adapted it to a high-throughput walkaway robotic microscopy platform. With this platform and medicinal chemistry approaches, we developed potent (nanomolar) compounds with novel chemistry that stimulate autophagy in rodent and human neuron and are protective in rodent and human neuron models of ALS and other neurodegenerative disorders. The molecules have drug-like properties, are orally bioavailable, have excellent blood-brain barrier penetration, and appear to be safe with chronic dosing. We are continuing to develop these molecules with the goal of choosing a clinical candidate for first-in-human trials.

Development of small-molecule autophagy inducers that mitigate neurodegeneration in models of ALS and other disorders

253rd National Meeting (2017)

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