Development of novel cytoprotective small compounds inhibiting mitochondria-dependent apoptosis

Author:

Matsuyama Mieko,Ortega Joseph T.,Fedorov Yuri,Scott-McKean Jonah,Muller-Greven Jeannie,Buck Matthias,Adams Drew,Jastrzebska Beata,Greenlee William,Matsuyama Shigemi

Abstract

AbstractWe identified cyto-protective small molecules (CSMs) by a cell-based high-throughput screening of Bax inhibitors. Through a medicinal chemistry program, M109S was developed, which is orally bioactive and penetrates the blood-brain/retina barriers. M109S protected retinal cells in the mouse models of Stargardt disease and macular degeneration. M109S directly interacted with Bax and inhibited the conformational change and mitochondrial translocation of Bax. M109S inhibited ABT-737-induced apoptosis both in Bax-only and Bak-only MEFs. M109S also inhibited apoptosis induced by staurosporine (mouse embryonic fibroblasts), etoposide (Neuro2a cells), and obatoclax (ARPE19 cells). M109S is a novel small molecule protecting cells from mitochondria-dependent apoptosis bothin vitroandin vivo. M109S has the potential to become a new research tool for studying cell death mechanisms and to develop therapeutics targeting mitochondria-dependent cell death pathway. (128words)

Publisher

Cold Spring Harbor Laboratory

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