Computer-aided design and synthesis of 3-carbonyl-5-phenyl-1H-pyrazole as highly selective and potent BRAFV600E and CRAF inhibitor.

Computer-aided design and synthesis of 3-carbonyl-5-phenyl-1H-pyrazole as highly selective and potent BRAFV600E and CRAF inhibitor.

Publication date: Dec 01, 2019

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 N-(3-(3-alkyl-1H-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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Kim, J., Choi, B., Im, D., Jung, H., Moon, H., Aman, W., and Hah, J.M. Computer-aided design and synthesis of 3-carbonyl-5-phenyl-1H-pyrazole as highly selective and potent BRAFV600E and CRAF inhibitor. 24976. 2019 J Enzyme Inhib Med Chem (34):1.

Concepts Keywords
Alkyl Cancer treatments
Amide Oncogenes
Aryl BRAF
BRAF Protein kinases
Cancer Tyrosine kinase inhibitors
Carbonyl Branches of biology
Computer Aided Design Cancer
ERK Enzymes
Heterodimer Melanoma
Inhibitor Cancer
MEK Melanoma
Melanoma Protein kinase inhibitor
Molecular Modelling Signal transduction
Paradox V600E
Phenyl
Phosphorylated
Pyrazole
RAS
Wild Type

Semantics

Type Source Name
drug DRUGBANK Rasagiline
disease MESH melanoma
pathway KEGG Melanoma
disease MESH cancer

Original Article

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