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Development of highly potent inhibitors of the ras-targeting human acyl protein thioesterases based on substrate similarity design |
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| Authors: | Hedberg Christian Dekker Frank J Rusch Marion Renner Steffen Wetzel Stefan Vartak Nachiket Gerding-Reimers Claas Bon Robin S Bastiaens Philippe I H Waldmann Herbert |
| Affiliation: | 1. Max‐Planck‐Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto‐Hahn‐Strasse 11, 44227 Dortmund (Germany);2. Technische Universit?t Dortmund, Fakult?t Chemie, Lehrbereich Chem. Biologie, Otto‐Hahn‐Strasse 6, 44227 Dortmund (Germany);3. Univ. of Groningen, University Centre for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen (The Netherlands);4. Novartis Pharma AG, Novartis Institute of Biomedical Research, 4056 Basel (Switzerland);5. Max‐Planck‐Institut für molekulare Physiologie, Abt. Systemische Zellbiologie, Otto‐Hahn‐Strasse 11, 44227 Dortmund (Germany);6. School of Chemistry, University of Leeds and Biomedical and Health Research Centre, LS2 9JT Leeds (UK) |
| Abstract: | A matter of common sense: A common recognition motif consisting of a negatively charged group five to six bonds away (red) from the (thio)ester functionality (green) and a positively charged tail group ten to twelve bonds away (blue) was identified in two native acyl protein thioesterase?1 (APT1) substrates. This similarity led to the design of potent inhibitors of the Ras-depalmitoylating enzyme APT1. |
| Keywords: | acyl protein thioesterase inhibitors ras protein signal transduction |
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