Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library

Authors:	Thutewohl Michael Kissau Lars Popkirova Boriana Karaguni Ionna-Maria Nowak Thorsten Bate Michael Kuhlmann Jürgen Müller Oliver Waldmann Herbert

Institution:	1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Str. 11, D-44227 Dortmund und Fachbereich 3, Organische Chemie, Universität Dortmund, Germany;2. Max-Planck-Institut für molekulare Physiologie, Abt. Strukturelle Biologie, Otto-Hahn-Str. 11, D-44227 Dortmund, Germany;3. AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK;1. School of Life Sciences, Shandong University of Technology, Zibo 255000, PR China;2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China;1. Nuclear Medicine Division, TRIUMF, Vancouver V6T 2A3, Canada;2. Diagnostics and Biomedical Technologies, GE Global Research, Niskayuna, NY 12309, USA;3. Department of Physics and Astronomy, University of British Columbia, Vancouver V6T 1Z1, Canada;4. Centre of Excellence for Functional Cancer Imaging, British Columbia Cancer Agency, Vancouver V5Z 4E6, Canada;5. Department of Radiology, Faculty of Medicine, University of British Columbia, Vancouver V5C 1M9, Canada;6. Experimental Therapeutics, British Columbia Cancer Agency, Vancouver V5Z 4E6, Canada;7. Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, University of British Columbia, Vancouver V6T 1Z3, Canada;1. Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan;2. Matsumoto Yushi-Seiyaku Co., Ltd, 2-1-3, Shibukawa-cho, Yao-City, Osaka 581-0075, Japan;1. Department of Electrical and Information Engineering, Hunan Institute of Engineering, Xiangtan 411101, China;2. School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China;1. Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea;3. Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA, Eumseong 369-873, Republic of Korea;4. Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea

Abstract:	A library of 51 analogues of the naturally occurring protein farnesyltransferase inhibitor pepticinnamin E was investigated biologically. Several compounds with pronounced inhibitory activity were discovered with the lowest IC(50) value reaching 1 microM. The library contains inhibitors which are competitive to either farnesylpyrophosphate or the peptide substrate and a bisubstrate inhibitor. This activity is supported and rationalized by molecular modelling experiments and different binding modes of the inhibitors deduced from them. Several compounds induced apoptosis in a Ras-transformed tumour cell line, and in one case this correlated with farnesyltransferase-inhibiting activity.

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