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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 screeningDiscovery of novel naphthalene-based diarylamides as pan-Raf kinase inhibitorsA. Elkamhawy et al.
被引：0
作者：
Ahmed Elkamhawy
[1
]
Usama M. Ammar
[2
]
Minkyoung Kim
[3
]
Anam Rana Gul
[4
]
Tae Jung Park
[4
]
Kyeong Lee
[3
]
机构：
[1] Nazarbayev University,Department of Chemistry, School of Sciences and Humanities
[2] Edinburgh Napier University,School of Applied Sciences
[3] Dongguk University-Seoul,BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy
[4] Chung-Ang University,Department of Chemistry, Research Institute of Chem
关键词：
Pan-Raf kinase inhibitors;
Drug design;
Naphthalene-based derivatives;
Difluoromethoxy group;
Anticancer drug;
Melanoma;
D O I：
10.1007/s12272-025-01533-5
中图分类号：
学科分类号：
摘要：
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.
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页码：150 / 165
页数：15
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