Time filter

Source Type

Kaschani F.,University of Duisburg - Essen | Clerc J.,University of Gottingen | Krahn D.,University of Duisburg - Essen | Bier D.,Chemical Genomics Center der Max Planck Gesellschaft | And 6 more authors.
Angewandte Chemie - International Edition | Year: 2012

Exceptionally specific: The natural-product-like structural complexity of a bicyclic hydantoin was exploited to generate the novel, highly specific activity-based profiling probe (ABPP) Mrl-Rh (Rh=rhodamine; see picture) for glyceraldehyde 3-phosphate dehydrogenases. This probe can be used to investigate activity changes of this enzyme class during plant-pathogen interactions. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Stolze S.C.,Chemical Genomics Center der Max Planck Gesellschaft | Stolze S.C.,University of Duisburg - Essen | Meltzer M.,University of Duisburg - Essen | Ehrmann M.,University of Duisburg - Essen | And 2 more authors.
Chemical Communications | Year: 2010

The solid phase total synthesis of the marine cyanobacterial Ahp-cyclodepsipeptide Symplocamide A is reported as a model for a general route for the synthesis of tailor-made non-covalent serine protease inhibitors. © The Royal Society of Chemistry 2010.


Vintonyak V.V.,Max Planck Institute For Molekulare Physiologie | Warburg K.,Max Planck Institute For Molekulare Physiologie | Warburg K.,TU Dortmund | Kruse H.,University of Munster | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2010

(Figure Presented) The best of 40000: Detailed structureactivity- relationship studies revealed key structural elements of indolin-2-on-3- spirothiazolidinones (see example) and their appropriate configuration for strong inhibitory activity against the pathophysiologically relevant title protein. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Krahn D.,University of Duisburg - Essen | Ottmann C.,Chemical Genomics Center der Max Planck Gesellschaft | Kaiser M.,University of Duisburg - Essen
Natural Product Reports | Year: 2011

Covering: up to March 2011 Syrbactin is a subordinate term for the syringolin, glidobactin and cepafungin natural product families. Their grouping is based on their related molecular frameworks, similar biosynthesis pathways and, most importantly, identical modes-of-action, being irreversible proteasome inhibition. With this report, we aim to review their chemical biology, describing their common, but also differential characteristics. © 2011 The Royal Society of Chemistry.


Schneider R.,Chemical Genomics Center der Max Planck Gesellschaft | Beumer C.,TU Dortmund | Simard J.R.,Chemical Genomics Center der Max Planck Gesellschaft | Grutter C.,TU Dortmund | And 2 more authors.
Journal of the American Chemical Society | Year: 2013

Normal cellular function, such as signal transduction, is largely controlled by the reversible phosphorylation of cellular proteins catalyzed by two major classes of enzymes, kinases and phosphatases. A misbalance in this complex and dynamic interplay leads to a variety of severe diseases, such as cancer, inflammation, or autoimmune diseases. This makes kinases as well as phosphatases equally attractive targets for therapeutic manipulation by small molecules. While the development of kinase inhibitors has resulted in several blockbuster drugs, such as imatinib, with remarkable success in the clinic and sales of many billions of U.S. dollars per year, not a single phosphatase inhibitor has yet been approved for clinical use. Similar to the kinase world, substrate-competitive phosphatase inhibitors have been developed but were not suitable for further development into clinical candidates due to their charge and limited selectivity. Research efforts, therefore, have shifted to the exploitation of allosteric sites that can regulate phosphatase activity and may enable the discovery of novel modulators of phosphatase activity with much improved pharmacological properties. However, assay systems, which enable the straightforward discovery of these inhibitor types, are missing. Here, we present a novel binding assay capable of detecting ligands of an allosteric pocket of the protein tyrosine phosphatase 1B. This assay is suitable for high-throughput screening and selectively detects ligands which bind to this unique site with a clear discrimination from substrate-competitive ligands. © 2013 American Chemical Society.


Clerc J.,Chemical Genomics Center der Max Planck Gesellschaft | Schellenberg B.,University of Zürich | Groll M.,TU Munich | Bachmann A.S.,University of Hawaii at Manoa | And 5 more authors.
European Journal of Organic Chemistry | Year: 2010

A convergent synthesis of SylA was developed and consists of the synthesis of a fully functionalized macrocycle, which is subsequently coupled with a urea moiety. For cyclization, ring-closing metathesis of a conformationally preorganized precursor was employed. The established synthetic route was then applied to the synthesis of SylA derivatives by using various peptidic side chains for decoration of the SylA macrocycle. The resulting collection of SylA analogues was tested for proteasome inhibition, revealing PEGylated SylA derivatives as the most potent proteasome inhibitors. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Archer C.R.,University of Hawaii at Manoa | Koomoa D.L.T.,University of Hawaii at Manoa | Mitsunaga E.M.,University of Hawaii at Manoa | Clerc J.,Chemical Genomics Center der Max Planck Gesellschaft | And 5 more authors.
Biochemical Pharmacology | Year: 2010

Syrbactins belong to a new class of proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established proteasome inhibitors, and bind the eukaryotic 20S proteasome by a novel mechanism. In this study, we examined the effects of syringolin A (SylA) and glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human neuroblastoma (SK-N-SH), human multiple myeloma (MM1.S, MM1.RL, and U266), and human ovarian cancer (SKOV-3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both dexamethasone-sensitive MM1.S cells (IC50: 0.004μM) and dexamethasone-resistant MM1.RL cells (IC50: 0.005μM). Syrbactins also inhibited the chymotrypsin-like proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC50: 0.015μM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of ubiquitinated proteins and tumor suppressor protein p53 and led to apoptotic cell death in a time-dependent manner. GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser473 and induced autophagy as judged by the presence of the lipidated form of microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective proteasome inhibitor class which promotes cell death. Proteasome inhibition is a promising strategy for targeted anticancer therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel, proteasome inhibitor-based drug therapeutics. © 2010 Elsevier Inc.


PubMed | Chemical Genomics Center der Max Planck Gesellschaft
Type: Journal Article | Journal: Chemical communications (Cambridge, England) | Year: 2010

The solid phase total synthesis of the marine cyanobacterial Ahp-cyclodepsipeptide Symplocamide A is reported as a model for a general route for the synthesis of tailor-made non-covalent serine protease inhibitors.


PubMed | Chemical Genomics Center der Max Planck Gesellschaft
Type: Journal Article | Journal: Journal of the American Chemical Society | Year: 2013

Normal cellular function, such as signal transduction, is largely controlled by the reversible phosphorylation of cellular proteins catalyzed by two major classes of enzymes, kinases and phosphatases. A misbalance in this complex and dynamic interplay leads to a variety of severe diseases, such as cancer, inflammation, or autoimmune diseases. This makes kinases as well as phosphatases equally attractive targets for therapeutic manipulation by small molecules. While the development of kinase inhibitors has resulted in several blockbuster drugs, such as imatinib, with remarkable success in the clinic and sales of many billions of U.S. dollars per year, not a single phosphatase inhibitor has yet been approved for clinical use. Similar to the kinase world, substrate-competitive phosphatase inhibitors have been developed but were not suitable for further development into clinical candidates due to their charge and limited selectivity. Research efforts, therefore, have shifted to the exploitation of allosteric sites that can regulate phosphatase activity and may enable the discovery of novel modulators of phosphatase activity with much improved pharmacological properties. However, assay systems, which enable the straightforward discovery of these inhibitor types, are missing. Here, we present a novel binding assay capable of detecting ligands of an allosteric pocket of the protein tyrosine phosphatase 1B. This assay is suitable for high-throughput screening and selectively detects ligands which bind to this unique site with a clear discrimination from substrate-competitive ligands.

Loading Chemical Genomics Center der Max Planck Gesellschaft collaborators
Loading Chemical Genomics Center der Max Planck Gesellschaft collaborators