Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 10, Pages 6877-6901Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00230
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Funding
- Korea Institution of Science and Technology (KIST) [2E30341, 2E31130]
- University of Sharjah [16011101018-P]
- CTCBIO Inc.
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In this study, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives with a terminal sulfonamide moiety were synthesized and their pan-RAF inhibitory effect was investigated. Compounds 27c and 38a showed the highest antiproliferative activity against cancer cells and were able to inhibit phosphorylation of MEK and ERK. Compound 38a was further tested for its in vivo activity against melanoma, and both cellular and animal activities were reported.
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 IC50 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.
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