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 A. Ammar U.M. Kim M. Gul A.R. Park T.J. Lee K.
February 2025 Pharmaceutical Society of Korea

Archives of Pharmacal Research
2025 #48 Issue 2 150 - 165 pp.

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-Raf^WT, B-Raf^V600E, 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.

Anticancer drug , Difluoromethoxy group , Drug design , Melanoma , Naphthalene-based derivatives , Pan-Raf kinase inhibitors

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Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Kabanbay Batyr 53, Astana, 010000, Kazakhstan
School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, 9 Sighthill Court, Edinburgh, EH11 4BN, United Kingdom
BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, South Korea
Department of Chemistry, Research Institute of Chem-Bio Diagnostic Technology, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul, 06974, South Korea

Department of Chemistry
School of Applied Sciences
BK21 FOUR Team and Integrated Research Institute for Drug Development
Department of Chemistry

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