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 and El-Gamal, Mohammed I. and Lee, Bong S. and Gamal El-Din, Mahmoud M. and Jeon, Hong R. and Kwon, Dow and Ammar, Usama M. and Mersal, Karim I. and Ali, Eslam M. H. and Lee, Kyung-Tae and Yoo, Kyung Ho and Han, Dong Keun and Lee, Jae Kyun and Kim, Garam and Choi, Hong Seok and Kwon, Young Jik and Lee, Kwan Hyi and Oh, Chang-Hyun (2021) Discovery of new Imidazo[2,1‑b]thiazole derivatives as potent pan-RAF inhibitors with promising in vitro and in vivo anti-melanoma activity. Journal of Medicinal Chemistry, 64 (10). pp. 6877-6901. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.1c00230)

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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 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.

ORCID iDs

Abdel-Maksoud, Mohammed, El-Gamal, Mohammed I., Lee, Bong S., Gamal El-Din, Mahmoud M., Jeon, Hong R., Kwon, Dow, Ammar, Usama M. ORCID logoORCID: https://orcid.org/0000-0002-7218-641X, 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 and Oh, Chang-Hyun;
CORE (COnnecting REpositories)