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15N CPMG Relaxation Dispersion for the Investigation of Protein Conformational Dynamics on the µs-ms Timescale
Published on: April 19, 2021
Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning
Toshihiro Aoki1, Ikumi Hyohdoh1, Noriyuki Furuichi1
1Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
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.
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