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

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).

• Authors: Junya Kawai, Masahiro Ota, Hitoshi Ohki, Tadashi Toki, Makoto Suzuki, Takashi Shimada, Satoshi Matsui, Hidekazu Inoue, Chika Sugihara, Norikazu Matsuhashi, Yumi Matsui, Sachiko Takaishi, Kiyoshi Nakayama
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 10 Issue 6 Pg. 893-898 (Jun 13 2019) ISSN: 1948-5875 [Print] United States
• PMID: 31223444 (Publication Type: Journal Article)