2. Academic Validation
  3. Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning

  • ACS Med Chem Lett. 2014 Jan 22;5(4):309-14. doi: 10.1021/ml400379x.
Toshihiro Aoki 1,  Ikumi Hyohdoh 1,  Noriyuki Furuichi 1,  Sawako Ozawa 1,  Fumio Watanabe 1,  Masayuki Matsushita 1,  Masahiro Sakaitani 1,  Kenji Morikami 2,  Kenji Takanashi 1,  Naoki Harada 1,  Yasushi Tomii 1,  Koji Shiraki 2,  Kentaro Furumoto 2,  Mitsuyasu Tabo 2,  Kiyoshi Yoshinari 1,  Kazutomo Ori 1,  Yuko Aoki 1,  Nobuo Shimma 1,  Hitoshi Iikura 3
Affiliations

Affiliations

  • 1 Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
  • 2 Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
  • 3 Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan ; Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
PMID: 24900832 DOI: 10.1021/ml400379x
Abstract

Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.

Keywords

CH5126766; MEK; Nitrogen scan; RO5126766; Raf; kinase inhibitor.

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