Development of novel cytoprotective small compounds inhibiting mitochondria-dependent cell death
Mieko Matsuyama,
Joseph T. Ortega,
Yuri Fedorov,
Jonah Scott-McKean,
Jeannie Muller-Greven,
Matthias Buck,
Drew Adams,
Beata Jastrzebska,
William Greenlee,
Shigemi Matsuyama
Affiliations
Mieko Matsuyama
Department of Ophthalmology and Visual Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Joseph T. Ortega
Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Yuri Fedorov
Department of Genetics and Genome Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Jonah Scott-McKean
Department of Ophthalmology and Visual Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Macromolecular Science and Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
Jeannie Muller-Greven
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Matthias Buck
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Drew Adams
Department of Genetics and Genome Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Beata Jastrzebska
Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
William Greenlee
Harrington Discovery Institute, Cleveland, OH 44106, USA
Shigemi Matsuyama
Department of Ophthalmology and Visual Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Division of Hematology and Oncology, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Corresponding author
Summary: We identified cytoprotective 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 ocular disease mouse models. 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 mouse embryonic fibroblasts. M109S also inhibited apoptosis induced by staurosporine, etoposide, and obatoclax. M109S decreased maximal mitochondrial oxygen consumption rate and reactive oxygen species production, whereas it increased glycolysis. These effects on cellular metabolism may contribute to the cytoprotective activity of M109S. M109S is a novel small molecule protecting cells from mitochondria-dependent apoptosis both in vitro and in vivo. M109S has the potential to become a research tool for studying cell death mechanisms and to develop therapeutics targeting mitochondria-dependent cell death pathway.
