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

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.

SUBMITTER: Aoki T

PROVIDER: S-EPMC4027752 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Aoki Toshihiro T Hyohdoh Ikumi I Furuichi Noriyuki N Ozawa Sawako S Watanabe Fumio F Matsushita Masayuki M Sakaitani Masahiro M Morikami Kenji K Takanashi Kenji K Harada Naoki N Tomii Yasushi Y Shiraki Koji K Furumoto Kentaro K Tabo Mitsuyasu M Yoshinari Kiyoshi K Ori Kazutomo K Aoki Yuko Y Shimma Nobuo N Iikura Hitoshi H

ACS medicinal chemistry letters 20140122 4

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 k ...[more]

PMID: 24900832

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Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties.

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Project description:BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.

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Upregulation of ERBB3 by FOXD3, an adaptive response to RAF and MEK inhibitors

Project description:To understand the transcriptional impact of FOXD3 in melanoma cells, we utilized a microarray approach. We collected RNA from three unrelated mutant B-RAF melanoma cell lines (WM115, WM793, and A375) that were engineered to inducibly express FOXD3 or the control gene, ?-galactosidase (LacZ), after 5 days of transgene induction. This time point was chosen based on maximal phenotypic changes previously observed. Comparison of gene signatures between the 3 cell lines produced approximately 2,600 common genes differentially regulated by FOXD3-expressing cells compared to the LacZ controls. Three unrelated mutant B-RAF melanoma cell lines (WM115, WM793, and A375) were induced to express FOXD3 and compared against the same cell lines expressing the control gene, ?-galactosidase (LacZ).

2013-03-31 | E-GEOD-43962 | biostudies-arrayexpress

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