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

Title
Design and synthesis of a new series of highly potent RAF kinase-inhibiting triarylpyrazole derivatives possessing antiproliferative activity against melanoma cells
Authors
오창현아쉬라프모하메트엘가말하메델최홍석
Keywords
A375; melanoma; RAF kinase
Issue Date
2016-12
Publisher
FUTURE MEDICINAL CHEMISTRY
Citation
VOL 18, NO 18-2211
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.
URI
http://pubs.kist.re.kr/handle/201004/66410
ISSN
1756-8919
Appears in Collections:
KIST Publication > Article
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