2. Academic Validation
  3. Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)

  • ACS Med Chem Lett. 2011 Feb 28;2(4):320-4. doi: 10.1021/ml200004g.
Hiroyuki Abe 1,  Shinichi Kikuchi 1,  Kazuhide Hayakawa 1,  Tetsuya Iida 1,  Noboru Nagahashi 1,  Katsuya Maeda 1,  Johei Sakamoto 1,  Noriaki Matsumoto 1,  Tomoya Miura 1,  Koji Matsumura 1,  Noriyoshi Seki 1,  Takashi Inaba 1,  Hisashi Kawasaki 1,  Takayuki Yamaguchi 1,  Reina Kakefuda 1,  Toyomichi Nanayama 1,  Hironori Kurachi 1,  Yoshikazu Hori 1,  Takayuki Yoshida 2,  Junya Kakegawa 2,  Yoshihiro Watanabe 2,  Aidan G Gilmartin 3,  Mark C Richter 3,  Katherine G Moss 3,  Sylvie G Laquerre 3
Affiliations

Affiliations

  • 1 Central Pharmaceutical Research Institute, Japan Tobacco, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 2 Pharmaceutical Frontier Research Laboratory, Japan Tobacco, 1-13-2 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
  • 3 Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
PMID: 24900312 DOI: 10.1021/ml200004g
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.

Keywords

GSK1120212; JTP-74057; MEK inhibitor; antiproliferative.

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