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

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

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).

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z