Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma.

Autor: Williams TE; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Subramanian S; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Verhagen J; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., McBride CM; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Costales A; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Sung L; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Antonios-McCrea W; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., McKenna M; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Louie AK; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Ramurthy S; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Levine B; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Shafer CM; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Machajewski T; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Renhowe PA; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Appleton BA; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Amiri P; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Chou J; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Stuart D; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Aardalen K; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States., Poon D; Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Aug 03; Vol. 6 (9), pp. 961-5. Date of Electronic Publication: 2015 Aug 03 (Print Publication: 2015).
DOI: 10.1021/ml500526p
Abstrakt: Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.
Databáze: MEDLINE