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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


Mohammed S. Abdel-Maksoud

Mohammed I. El-Gamal

Bong S. Lee

Mahmoud M. Gamal El-Din

Hong R. Jeon

Dow Kwon

Karim I. Mersal

Eslam M. H. Ali

Kyung-Tae Lee

Kyung Ho Yoo

Dong Keun Han

Jae Kyun Lee

Garam Kim

Hong Seok Choi

Young Jik Kwon

Kwan Hyi Lee

Chang Hyun Oh


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
Public URL