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.

Keywords::

• A375
• docking
• melanoma
• pyrazole
• RAF kinase

Financial & competing interests disclosure

This work was supported by Korea Institute of Science and Technology (KIST), KIST Project (2E25260). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by Korea Institute of Science and Technology (KIST), KIST Project (2E25260). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.