Treatment of autophagy deficits in Charcot-Marie-Tooth disease caused by mutations in the small heat shock proteins HSPB1 and HSPB8.

Autophagy is a normal physiological process that removes unnecessary or dysfunctional cellular components from the cytoplasm. Defective autophagy is currently emerging as a hallmark feature of many diseases, including Charcot-Marie-Tooth (CMT) neuropathy. In this framework, basic research and drug development have a strong need for reliable, drug-like autophagy inducers. We carried out a phenotypic high-throughput screen on compounds that were preselected based on drug likeness parameters. In total, 3 distinct chemical families were identified that previously have not been associated with autophagy induction. After thorough validation, potency and gross mode-of-action studies, the most promising chemical family was prioritized. Structure-activity relationships will be constructed for this chemical family. In addition, chemical optimization will be pursued to obtain novel representatives with further improved potency and a maximally favorable physicochemical profile. Efforts will be done for target finding. All novel compounds will be thoroughly investigated in a cell model for CMT neuropathy associated with mutations in the small heat shock proteins HSPB1 and HSPB8. To fully characterize this translational potential, in vivo evaluation in an established mouse model will be carried out for one maximally optimized compound.

Keywords:AUTOPHAGY, MEDICINAL CHEMISTRY, CHARCOT-MARIE-TOOTH DISEASE, SMALL MOLECULES

Disciplines:Proteins, Drug discovery and development not elsewhere classified, Medicinal chemistry, Neurological and neuromuscular diseases