Discovery of New Imidazo[2,1-b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising In Vitro and In Vivo Anti-melanoma Activity

Abdel-Maksoud, Mohammed S.; El-Gamal, Mohammed I.; Lee, Bong S.; Gamal El-Din, Mahmoud M.; Jeon, Hong R.; Kwon, Dow; Ammar, Usama M.; Mersal, Karim I.; Ali, Eslam M. H.; Lee, Kyung-Tae; Yoo, Kyung Ho; Han, Dong Keun; Lee, Jae Kyun; Kim, Garam; Choi, Hong Seok; Kwon, Young Jik; Lee, Kwan Hyi; Oh, Chang Hyun

Abstract

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure−activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC 50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.

• Journal Article Type: Article
• Online Publication Date: May 17, 2021
• Publication Date: May 27, 2021
• Deposit Date: Dec 11, 2022
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 64
• Issue: 10
• Pages: 6877-6901
• DOI: https://doi.org/10.1021/acs.jmedchem.1c00230
• Public URL: http://researchrepository.napier.ac.uk/Output/2973678