Kinetic High Throughput Screening for Agonists and Inhibitors of the TRPML1 Ion channel

National Center For Advancing Translational Sciences

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Abstract

Mutations or expression deficiency of the TRPML1 channel have been found to cause several devastating lysosomal storage disorders, namely mucolipidosis 4 (ML4) and Niemann-Pick type C (NPC) disease. This collaborative team aims to identify compounds that are capable of modulating TRPML1 activity, providing potential therapies for these lysosomal diseases. During this period, ETB has worked to characterize and expand the most promising identified chemotypes through medicinal chemistry. In the last year the efforts have been focused in increasing the metabolic stability of the lead molecules. Some of the new optimized compounds display good potency, proper stability and good pharmacokinetics including brain penetration. Select compound will be evaluated in vivo in efficacy studies