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Discovery of novel naphthalene-based diarylamides as pan-Raf kinase inhibitors with promising anti-melanoma activity: rational design, synthesis, in vitro and in silico screening

Elkamhawy, Ahmed; Ammar, Usama M.; Kim, Minkyoung; Gul, Anam Rana; Park, Tae Jung; Lee, Kyeong

Authors

Ahmed Elkamhawy

Minkyoung Kim

Anam Rana Gul

Tae Jung Park

Kyeong Lee



Abstract

Raf kinase enzymes are often dysregulated in melanoma. While sorafenib demonstrates strong activity against wild-type B-Raf, it fails to effectively inhibit the mutated form of B-Raf. In this study, sorafenib served as a lead compound for the development of new derivatives designed to enhance inhibitory activity across multiple Raf isoforms (pan-Raf inhibitors). Novel naphthalene-based diarylamide derivatives were subsequently designed, synthesized, and evaluated for their biological activity against various Raf kinase isoforms and the melanoma A375 cell line. Among these, compound 9a, containing a difluoromethoxy group, demonstrated strong inhibitory activity across B-RafWT, B-RafV600E, and c-Raf. Additionally, it induced G2/M phase arrest and triggered dose-dependent apoptosis, effectively suppressing both cell proliferation and survival. Compound 9a also exhibited high selectivity for Raf isoforms with minimal off-target effects, underscoring its specificity and therapeutic potential for Raf-driven malignancies.

Citation

Elkamhawy, A., Ammar, U. M., Kim, M., Gul, A. R., Park, T. J., & Lee, K. (2025). Discovery of novel naphthalene-based diarylamides as pan-Raf kinase inhibitors with promising anti-melanoma activity: rational design, synthesis, in vitro and in silico screening. Archives of Pharmacal Research, 48(2), 150-165. https://doi.org/10.1007/s12272-025-01533-5

Journal Article Type Article
Acceptance Date Jan 16, 2025
Online Publication Date Feb 8, 2025
Publication Date 2025
Deposit Date Feb 11, 2025
Publicly Available Date Feb 11, 2025
Journal Archives of Pharmacal Research
Print ISSN 0253-6269
Electronic ISSN 1976-3786
Publisher Springer
Peer Reviewed Peer Reviewed
Volume 48
Issue 2
Pages 150-165
DOI https://doi.org/10.1007/s12272-025-01533-5
Keywords Pan-Raf kinase inhibitors, Drug design, Naphthalene-based derivatives, Difuoromethoxy group, Anticancer drug, Melanoma
Public URL http://researchrepository.napier.ac.uk/Output/4114761

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