Design and synthesis of a new series of highly potent RAF kinase-inhibiting triarylpyrazole derivatives possessing antiproliferative activity against melanoma cells.

Abstract

BACKGROUND:

Inhibition of V600E-B-RAF kinase represents a potential avenue for melanoma treatment. Herein, a series of 1,3,4-triarylpyrazoles possessing amide linker were designed, synthesized and evaluated for RAF kinase inhibition.

RESULTS:

Compounds 1d and 1f were more potent than sorafenib against A375 cell line, and their selectivity indexes toward A375 than HS27 fibroblasts were 25.43 and 45.83, respectively. Compound 1f was more potent against the melanoma cell lines with B-RAF V600E mutation than melanoma cells with NRAS mutation and normal skin epithelial cells. Compounds 1d and 1f showed strong potency and selectivity against V600E-B-RAF kinase with IC50 values of 3.80 and 2.98 nM, respectively. Molecular docking studies revealed their binding mode.

CONCLUSION:

Potent and selective V600E-B-RAF antimelanoma agents were discovered. [Formula: see text].

• Authors: Mohammad Ashrafuddin Khan, Mohammed I El-Gamal, Hamadeh Tarazi, Hong Seok Choi, Chang-Hyun Oh
• Journal: Future medicinal chemistry (Future Med Chem) Vol. 8 Issue 18 Pg. 2197-2211 (12 2016) ISSN: 1756-8927 [Electronic] England
• PMID: 27845592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrazoles
• Proto-Oncogene Proteins B-raf

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Melanoma (drug therapy, pathology)
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, metabolism)
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship