Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold

  • ACS Med Chem Lett. 2019 May 24;10(6):893-898. doi: 10.1021/acsmedchemlett.9b00069.
Junya Kawai  1 ,  Masahiro Ota  2 ,  Hitoshi Ohki  1 ,  Tadashi Toki  1 ,  Makoto Suzuki  2 ,  Takashi Shimada  2 ,  Satoshi Matsui  1 ,  Hidekazu Inoue  1 ,  Chika Sugihara  2 ,  Norikazu Matsuhashi  2 ,  Yumi Matsui  2 ,  Sachiko Takaishi  1 ,  Kiyoshi Nakayama  3
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2. Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 3. Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan.
PMID: 31223444 DOI: 10.1021/acsmedchemlett.9b00069
Abstract

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of Cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in Cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE).

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