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

Autor:	Abdel-Maksoud MS; Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Dokki, Giza 12622, Egypt., El-Gamal MI; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt., Lee BS; CTC SCIENCE, 38, Hyundaikia-ro, Paltan-myeon, Hwaseong-si, Gyeonggi-do 18576, Republic of Korea., Gamal El-Din MM; Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Dokki, Giza 12622, Egypt., Jeon HR; CTCBIO Inc., 450-34, Noha-ri, Paltan-myeon, Hwaseong-si, Gyeonggi-do 18576, Republic of Korea., Kwon D; CTC SCIENCE, 38, Hyundaikia-ro, Paltan-myeon, Hwaseong-si, Gyeonggi-do 18576, Republic of Korea., Ammar UM; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom., Mersal KI; Center for Biomaterials, Korea Institute of Science & Technology (KIST), Seongbuk-gu, Hwarangro 14-gil 5, Seoul 136-791, Seoul, Republic of Korea.; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea., Ali EMH; Center for Biomaterials, Korea Institute of Science & Technology (KIST), Seongbuk-gu, Hwarangro 14-gil 5, Seoul 136-791, Seoul, Republic of Korea.; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea., Lee KT; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea., Yoo KH; Chemical Kinomics Research Center, Korea Institute of Science & Technology (KIST), Seoul 136-791, Republic of Korea., Han DK; Department of Biomedical Science, CHA University, Gyeonggi 13488, Republic of Korea., Lee JK; Center for Neuro-Medicine, Korea Institute of Science & Technology (KIST), Seongbuk-gu, Hwarangro 14-gil 5, Seoul 136-791, Seoul, Republic of Korea., Kim G; College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea., Choi HS; College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea., Kwon YJ; Department of Chemical Engineering and Materials Science, University of California, Irvine, California 92697, United States.; Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, United States., Lee KH; Center for Biomaterials, Korea Institute of Science & Technology (KIST), Seongbuk-gu, Hwarangro 14-gil 5, Seoul 136-791, Seoul, Republic of Korea.; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea., Oh CH; Center for Biomaterials, Korea Institute of Science & Technology (KIST), Seongbuk-gu, Hwarangro 14-gil 5, Seoul 136-791, Seoul, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 May 27; Vol. 64 (10), pp. 6877-6901. Date of Electronic Publication: 2021 May 17.
DOI:	10.1021/acs.jmedchem.1c00230
Abstrakt:	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.
Databáze:	MEDLINE
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