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

doi:10.1016/j.isci.2023.107916

Development of novel cytoprotective small compounds inhibiting mitochondria-dependent cell death

iScience. 2023 Sep 17;26(10):107916. doi: 10.1016/j.isci.2023.107916. eCollection 2023 Oct 20.

Authors

Mieko Matsuyama¹, Joseph T Ortega², Yuri Fedorov³, Jonah Scott-McKean^{1

4}, Jeannie Muller-Greven⁵, Matthias Buck⁵, Drew Adams³, Beata Jastrzebska², William Greenlee⁶, Shigemi Matsuyama^{1

2

7

8

9}

Affiliations

¹ Department of Ophthalmology and Visual Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
² Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
³ Department of Genetics and Genome Science, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
⁴ Department of Macromolecular Science and Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
⁵ Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
⁶ Harrington Discovery Institute, Cleveland, OH 44106, USA.
⁷ Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
⁸ Division of Hematology and Oncology, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
⁹ Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.

Abstract

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.

Keywords: Cell biology; Cellular physiology; Chemistry.

Abstract

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