title: Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate).
abstract: Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Iida
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Nagahashi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Johei
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Miura
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Seki
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kawasaki
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Kakefuda
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Toyomichi
authors.initials: T
authors.lastname: Nanayama
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kurachi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Pharmaceutical Frontier Research Laboratory, Japan Tobacco, 1-13-2 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Pharmaceutical Frontier Research Laboratory, Japan Tobacco, 1-13-2 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kakegawa
authors.affiliation: Pharmaceutical Frontier Research Laboratory, Japan Tobacco, 1-13-2 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Aidan G
authors.initials: AG
authors.lastname: Gilmartin
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Richter
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Moss
authors.affiliation: Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Laquerre
keywords: GSK1120212; JTP-74057; MEK inhibitor; antiproliferative