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
  • 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.

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