Discovery of potential RAF selective back pocket as a promising biological site for BRAF inhibitors targeting resistant melanoma opens the door for a new generation of kinase inhibitors: Design, synthesis, biological evaluation, and in silico molecular simulation

Ammar, Usama; El-Din, Mahmoud Gamal; Abdel-Maksoud, Mohammed; Ali, Eslam; El-Gamal, Mohammed; Mahmoud, Zeyad; Ahn, Sunjoo; Nguyen, Nhung Hong; Kim, Eunkyoung; Jun, Park Su; Deug, Kim Young; Choi, Hong Seok; Lee, Kwan Hyi; Choi, Gahyeon; Oh, Chang-Hyun

Abstract

Despite the approved combination of BRAFV600E and MEK inhibitors to treat drug-resistant melanoma, serious side effects associated with this combination have been reported, particularly referring to MEK inhibitors. In the current study, an isosteric drug design strategy and were applied leading to the discovery of KS16, a highly potent candidate with a developed pharmacokinetic profile. KS16 exhibited superior efficacy in inhibiting drug-resistant melanoma cell proliferation as a single agent. KS16 displayed a selective cytotoxic profile against melanoma cell lines over other types of cancer cell lines and inhibited RAF kinases over other protein kinases. It showed potent in vivo activity against melanoma-bearing animal models. In silico molecular docking revealed potential hydrophobic interactions with RAF selective back pocket. KS16 demonstrated improved microsomal stability, half-life, and bioavailability. It exhibited an improved safety profile over normal skin cell lines and hERG protein. Our ultimate future direction is to generate an advanced lead candidate.

Citation

Ammar, U., El-Din, M. G., Abdel-Maksoud, M., Ali, E., El-Gamal, M., Mahmoud, Z., Ahn, S., Nguyen, N. H., Kim, E., Jun, P. S., Deug, K. Y., Choi, H. S., Lee, K. H., Choi, G., & Oh, C.-H. (2025). Discovery of potential RAF selective back pocket as a promising biological site for BRAF inhibitors targeting resistant melanoma opens the door for a new generation of kinase inhibitors: Design, synthesis, biological evaluation, and in silico molecular simulation. International Journal of Biological Macromolecules, 320(Part 2), Article 145699. https://doi.org/10.1016/j.ijbiomac.2025.145699

• Journal Article Type: Article
• Acceptance Date: Jun 30, 2025
• Online Publication Date: Jul 7, 2025
• Publication Date: 2025-08
• Deposit Date: Jul 8, 2025
• Publicly Available Date: Jul 8, 2025
• Journal: International Journal of Biological Macromolecules
• Print ISSN: 0141-8130
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 320
• Issue: Part 2
• Article Number: 145699
• DOI: https://doi.org/10.1016/j.ijbiomac.2025.145699
• Keywords: BRAF kinase, Resistant melanoma, RAF back pocket, Drug design