Computer-aided design and synthesis of 3-carbonyl-5-phenyl-1 H -pyrazole as highly selective and potent BRAFV600E and CRAF inhibitor
BRAF belongs to the upstream portion of the MAPK pathway, which is involved in cell proliferation and survival. When mutations occur in BRAF, downstream MEK and ERK are phosphorylated irrespective of RAS, resulting in melanoma-like cancer. Over the years, small molecules targeting BRAFV600E have bee...
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Published in | Journal of enzyme inhibition and medicinal chemistry Vol. 34; no. 1; pp. 1314 - 1320 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.12.2019
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Subjects | |
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Abstract | BRAF belongs to the upstream portion of the MAPK pathway, which is involved in cell proliferation and survival. When mutations occur in BRAF, downstream MEK and ERK are phosphorylated irrespective of RAS, resulting in melanoma-like cancer. Over the years, small molecules targeting BRAFV600E have been discovered to be very effective melanoma drugs, but they are known to cause the BRAF paradox. Recently, it was shown that this paradox is caused by the heterodimer phenomenon of BRAF/CRAF. Here, we suggest one method by which paradoxical activation can be avoided by selectively inhibiting BRAFV600E and CRAF but not wild-type BRAF. From previous report of
-(3-(3-alkyl-1
-pyrazol-5-yl) phenyl) aryl amide as a selective inhibitor of BRAFV600E and CRAF, we present compounds that offer enhanced selectivity and efficacy with the aid of molecular modelling. |
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AbstractList | BRAF belongs to the upstream portion of the MAPK pathway, which is involved in cell proliferation and survival. When mutations occur in BRAF, downstream MEK and ERK are phosphorylated irrespective of RAS, resulting in melanoma-like cancer. Over the years, small molecules targeting BRAFV600E have been discovered to be very effective melanoma drugs, but they are known to cause the BRAF paradox. Recently, it was shown that this paradox is caused by the heterodimer phenomenon of BRAF/CRAF. Here, we suggest one method by which paradoxical activation can be avoided by selectively inhibiting BRAFV600E and CRAF but not wild-type BRAF. From previous report of
-(3-(3-alkyl-1
-pyrazol-5-yl) phenyl) aryl amide as a selective inhibitor of BRAFV600E and CRAF, we present compounds that offer enhanced selectivity and efficacy with the aid of molecular modelling. |
Author | Aman, Waqar Moon, Hyungwoo Choi, Byeongha Im, Daseul Kim, Jinwoong Hah, Jung-Mi Jung, Hoyong |
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SubjectTerms | Computer-Aided Design Dose-Response Relationship, Drug Humans Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - metabolism Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Structure-Activity Relationship |
Title | Computer-aided design and synthesis of 3-carbonyl-5-phenyl-1 H -pyrazole as highly selective and potent BRAFV600E and CRAF inhibitor |
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