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Baggelaar M.P.,University of Groningen | Huang Y.,University of Groningen | Feringa B.L.,University of Groningen | Dekker F.J.,Groningen Research Institute of Pharmacy | Minnaard A.J.,University of Groningen
Bioorganic and Medicinal Chemistry | Year: 2013

A catalytic asymmetric synthesis of (S)-(-)-zearalenone is reported using asymmetric allylic alkylation for the introduction of the stereocenter. (S)-(-)-Zearalenone turned out to be a novel lipoxygenase inhibitor. © 2013 Elsevier Ltd. All rights reserved. Source


Kiuchi T.,Kings College London | Kiuchi T.,Tohoku University | Ortiz-Zapater E.,Kings College London | Monypenny J.,Kings College London | And 33 more authors.
Science Signaling | Year: 2014

The epidermal growth factor receptor (EGFR) is a member of the ErbB family that can promote the migration and proliferation of breast cancer cells. Therapies that target EGFR can promote the dimerization of EGFR with other ErbB receptors, which is associated with the development of drug resistance. Understanding how interactions among ErbB receptors alter EGFR biology could provide avenues for improving cancer therapy. We found that EGFR interacted directly with the CYT1 and CYT2 variants of ErbB4 and the membrane-anchored intracellular domain (mICD). The CYT2 variant, but not the CYT1 variant, protected EGFR from ligand-induced degradation by competing with EGFR for binding to a complex containing the E3 ubiquitin ligase c-Cbl and the adaptor Grb2. Cultured breast cancer cells overexpressing both EGFR and ErbB4 CYT2 mICD exhibited increased migration. With molecular modeling, we identified residues involved in stabilizing the EGFR dimer. Mutation of these residues in the dimer interface destabilized the complex in cells and abrogated growth factor-stimulated cell migration. An exon array analysis of 155 breast tumors revealed that the relative mRNA abundance of the ErbB4 CYT2 variant was increased in ER+ HER2- breast cancer patients, suggesting that our findings could be clinically relevant. We propose a mechanism whereby competition for binding to c-Cbl in an ErbB signaling heterodimer promotes migration in response to a growth factor gradient. Source


Dekker F.J.,Groningen Research Institute of Pharmacy | Hedberg C.,Max Planck Institute of Molecular Physiology
Bioorganic and Medicinal Chemistry | Year: 2011

The H- and N-Ras GTPases are prominent examples of proteins, whose localizations and signalling capacities are regulated by reversible palmitoylations and depalmitoylations. Recently, the novel small molecule inhibitor palmostatin B has been described to inhibit Ras depalmitoylation and to revert the phenotype of oncogenic HRasG12V transformed cells. This demonstrates that palmostatin B is a tool to investigate the biochemical effects of the inhibition of cellular Ras depalmitoylation on Ras signalling, which is relevant for oncology. Furthermore, it is to be expected that many proteins, of which the signalling capacities depend on reversible palmitoylation, will be discovered in the near future. This stresses the urgent need for further development of small molecule inhibitors of palmitoylation and depalmitoylation in order to study their functions in cellular signalling. © 2011 Elsevier Ltd. All rights reserved. Source


Eelderink-Chen Z.,Chromatin | Olmedo M.,Institute of Medical Psychology | Olmedo M.,Andalusian Center for Developmental Biology | Bosman J.,Groningen Research Institute of Pharmacy | Merrow M.,Institute of Medical Psychology
Methods in Enzymology | Year: 2015

Three properties are most often attributed to the circadian clock: a ca. 24-h free-running rhythm, temperature compensation of the circadian rhythm, and its entrainment to zeitgeber cycles. Relatively few experiments, however, are performed under entrainment conditions. Rather, most chronobiology protocols concern constant conditions. We have turned this paradigm around and used entrainment to study the circadian clock in organisms where a free-running rhythm is weak or lacking. We describe two examples therein: Caenorhabditis elegans and Saccharomyces cerevisiae. By probing the system with zeitgeber cycles that have various structures and amplitudes, we can demonstrate the establishment of systematic entrained phase angles in these organisms. We conclude that entrainment can be utilized to discover hitherto unknown circadian clocks and we discuss the implications of using entrainment more broadly, even in model systems that show robust free-running rhythms. © 2015 Elsevier Inc. All rights reserved. Source


Ghizzoni M.,Groningen Research Institute of Pharmacy | Boltjes A.,Groningen Research Institute of Pharmacy | Graaf C.D.,VU University Amsterdam | Haisma H.J.,Groningen Research Institute of Pharmacy | Dekker F.J.,Groningen Research Institute of Pharmacy
Bioorganic and Medicinal Chemistry | Year: 2010

Several lines of evidence indicate that histone acetyltransferases (HATs) are novel drug targets for treatment of diseases like, for example, cancer and inflammation. The natural product anacardic acid is a starting point for development of small molecule inhibitors of the histone acetyltransferase (HAT) p300/CBP associated factor (PCAF). In order to optimize the inhibitory potency, a binding model for PCAF inhibition by anacardic acid was proposed and new anacardic acid derivatives were designed. Ten new derivatives were synthesized using a novel synthetic route. One compound showed a twofold improved inhibitory potency for the PCAF HAT activity and a twofold improved inhibition of histone acetylation in HEP G2 cells. © 2010 Elsevier Ltd. All rights reserved. Source

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