2. Academic Validation
  3. Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis

Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis

  • ACS Med Chem Lett. 2019 Jul 30;10(9):1272-1278. doi: 10.1021/acsmedchemlett.9b00142.
Kosuke Dodo 1 2 3,  Erika Kuboki 4,  Tadashi Shimizu 1 3,  Ryu Imamura 5,  Megumi Magarisawa 4,  Masahiro Takahashi 3,  Takuto Tokuhiro 4,  Satoshi Yotsumoto 4,  Kenichi Asano 4,  Shuhei Nakao 1,  Naoki Terayama 1,  Takashi Suda 5,  Masato Tanaka 4,  Mikiko Sodeoka 1 2 3
Affiliations

Affiliations

  • 1 Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
  • 2 Sodeoka Live Cell Chemistry Project, ERATO, JST, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
  • 3 Institute of Multidisciplinary Research for Advanced Materials (IMRAM), Tohoku University, 2-1-1, Katahira, Aoba, Sendai, Miyagi 980-8577, Japan.
  • 4 Laboratory of Immune Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan.
  • 5 Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
PMID: 31531196 DOI: 10.1021/acsmedchemlett.9b00142
Abstract

The indolylmaleimide (IM) derivative IM-17 shows inhibitory activity against oxidative-stress-induced necrotic cell death and cardioprotective activity in rat ischemia-reperfusion injury models. In order to develop a more potent derivative, we conducted a detailed structure-activity relationship study of IM derivatives and identified IM-93 as the most potent derivative with good water solubility. IM-93 inhibited Ferroptosis and NETosis, but not Necroptosis or Pyroptosis. In contrast, ferrostatin-1 (Fer-1), a Ferroptosis inhibitor, did not inhibit NETosis, although the accompanying lipid peroxidation was partially inhibited by Fer-1, as well as by IM-93. Thus, IM derivatives have a unique activity profile and appear to be promising candidates for in vivo application.

Figures
Products