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Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity by Junya Kawai; Tadashi Toki; Masahiro Ota; Hidekazu Inoue; Yoshimi Takata; Takashi Asahi; Makoto Suzuki; Takashi Shimada; Kaori Ono; Kanae Suzuki; Sachiko Takaishi; Hitoshi Ohki; Satoshi Matsui; Shinji Tsutsumi; Yasuhide Hirota; Kiyoshi Nakayama is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity about?

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead . X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.

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Author

Junya Kawai; Tadashi Toki; Masahiro Ota; Hidekazu Inoue; Yoshimi Takata; Takashi Asahi; Makoto Suzuki; Takashi Shimada; Kaori Ono; Kanae Suzuki; Sachiko Takaishi; Hitoshi Ohki; Satoshi Matsui; Shinji Tsutsumi; Yasuhide Hirota; Kiyoshi Nakayama

Published

2019

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)