Publications by authors named "Ulrike Gross"

9 Publications

  • Page 1 of 1

Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule.

J Med Chem 2019 01 12;62(1):306-316. Epub 2018 Sep 12.

Department of Molecular Immunology , Beckman Research Institute of the City of Hope , 1500, E. Duarte Road , Duarte , California 91010 , United States.

Protein tyrosine phosphatase non-receptor type 5 (PTPN5, STEP) is a brain specific phosphatase that regulates synaptic function and plasticity by modulation of N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Dysregulation of STEP has been linked to neurodegenerative and neuropsychiatric diseases, highlighting this enzyme as an attractive therapeutic target for drug discovery. Selective targeting of STEP with small molecules has been hampered by high conservation of the active site among protein tyrosine phosphatases. We report the discovery of the first small molecule allosteric activator for STEP that binds to the phosphatase domain. Allosteric binding is confirmed by both X-ray and N NMR experiments, and specificity has been demonstrated by an enzymatic test cascade. Molecular dynamics simulations indicate stimulation of enzymatic activity by a long-range allosteric mechanism. To allow the scientific community to make use of this tool, we offer to provide the compound in the course of an open innovation initiative.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00857DOI Listing
January 2019

Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators.

Bioorg Med Chem 2018 07 30;26(12):3227-3241. Epub 2018 Apr 30.

Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany.

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.
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http://dx.doi.org/10.1016/j.bmc.2018.04.053DOI Listing
July 2018

Colorectal Choriocarcinoma in a Patient with Probable Lynch Syndrome.

Front Oncol 2016 29;6:252. Epub 2016 Nov 29.

Cantonal Hospital Baselland, Institute of Pathology , Liestal , Switzerland.

Background: Personalized therapy of colorectal cancer is influenced by morphological, molecular, and host-related factors. Here, we report the comprehensive clinicopathological and molecular analysis of an extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome.

Case Presentation: A 61-year-old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. A right hemicolectomy was performed. Histopathological analysis showed a mixed trophoblastic and syncytiotrophoblastic differentiation, consistent with choriocarcinoma. Disease progression was rapid under oxaliplatin, capecitabine, irinotecan, and bevacizumab. Molecular phenotyping identified loss of mismatch-repair protein immunostaining for PMS2, microsatellite instability, a lack of MLH1 promoter methylation, and lack of BRAF mutation suggestive of Lynch syndrome. Targeted next-generation sequencing revealed an ataxia telangiectasia mutated (p.P604S) missense mutation. A bleomycin, etoposide, and cisplatin treatment protocol targeting germ cell neoplasia lead to disease remission and prolonged survival of 34 months.

Conclusion: Comprehensive immunohistochemical and genetic testing is essential to identify uncommon cancers possibly related to Lynch syndrome. For rare tumors, personalized therapeutic approaches should take both molecular and morphological information into account.
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http://dx.doi.org/10.3389/fonc.2016.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126084PMC
November 2016

Reconsidering pluripotency tests: do we still need teratoma assays?

Stem Cell Res 2013 Jul 26;11(1):552-62. Epub 2013 Mar 26.

SET Foundation, Frankfurt am Main, Germany.

The induction of teratoma in mice by the transplantation of stem cells into extra-uterine sites has been used as a read-out for cellular pluripotency since the initial description of this phenomenon in 1954. Since then, the teratoma assay has remained the assay of choice to demonstrate pluripotency, gaining prominence during the recent hype surrounding human stem cell research. However, the scientific significance of the teratoma assay has been debated due to the fact that transplanted cells are exposed to a non-physiological environment. Since many mice are used for a result that is heavily questioned, it is time to reconsider the teratoma assay from an ethical point of view. Candidate alternatives to the teratoma assay comprise the directed differentiation of pluripotent stem cells into organotypic cells, differentiation of cells in embryoid bodies, the analysis of pluripotency-associated biomarkers with high correlation to the teratoma forming potential of stem cells, predictive epigenetic footprints, or a combination of these technologies. Each of these assays is capable of addressing one or more aspects of pluripotency, however it is essential that these assays are validated to provide an accepted robust, reproducible alternative. In particular, the rapidly expanding number of human induced pluripotent stem cell lines, requires the development of simple, affordable standardized in vitro and in silico assays to reduce the number of animal experiments performed.
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http://dx.doi.org/10.1016/j.scr.2013.03.001DOI Listing
July 2013

Guidance on determining indispensability and balancing potential benefits of animal experiments with costs to the animals with specific consideration of EU directive 2010/63/EU.

ALTEX 2012 ;29(2):219-28

Institut für angewandte Zellkultur, Munich, Germany.

Within the context of a workshop, a concept and practical guidance were developed that seek to balance potential benefits of animal experiments to humans, other animals, and the environment against the pain, suffering, and distress caused to the experimental animals. The aim was to achieve transparent decisions that can be communicated in a concise manner that is accessible to a layperson and is in accordance with German national law and EU Directive 2010/63/EU. The steps of the resulting decision process deal with the classification of procedures into the four severity levels, the consideration of humane endpoints, determination of the indispensability of the procedure on the basis of sound scientific argument, classification into applied or basic research, determination of the probability of success in the case of applied research, and the cost-benefit analysis, culminating in a decision on the approval or denial of the procedure.
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http://dx.doi.org/10.14573/altex.2012.2.219DOI Listing
September 2012

Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration.

Org Biomol Chem 2011 Oct 26;9(20):6903-8. Epub 2011 Aug 26.

Whiffen Laboratory, University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW.

We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situ FTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.
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http://dx.doi.org/10.1039/c1ob06017aDOI Listing
October 2011

A unified strategy targeting the thiodiketopiperazine mycotoxins exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin.

Chemistry 2010 Oct 31;16(38):11624-31. Epub 2010 Aug 31.

Institut für Organische Chemie, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany.

A unified synthetic strategy directed towards mycotoxins belonging to the thiodiketopiperazine family is reported. The building blocks for a number of natural products--including exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin--have been synthesised stereoselectively from a common precursor. This key intermediate was constructed through an efficient and highly diastereoselective [2+2] cycloaddition between a ketene and an enecarbamate derived from L-pyroglutamic acid. The annelation of the second ring was accomplished through ring-closing metathesis and enol ether-olefin ring-closing metathesis to provide both cis- and trans-annelated azabicyclic cyclohexenones, as well as an annelated seven-membered cyclic enol ether. A Pd-catalysed elimination of allyl acetate gave rise to the cyclohexadienol structure of gliotoxin. Dimerisation of one building block to afford the diketopiperazine core was demonstrated.
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http://dx.doi.org/10.1002/chem.201001169DOI Listing
October 2010

Stereoselective synthesis of the epicoccin core.

Org Lett 2009 Oct;11(20):4740-2

Institute of Organic Chemistry, Karlsruhe Institute of Technology, Germany.

A short, convergent, and asymmetric synthesis of the epicoccin core was achieved using a phosphite-promoted one-step condensation of a complex proline-type amino acid. Key features of the assembly of this amino acid were a double-bond isomerization/vinylation/ring-closing metathesis strategy as well as an efficient, highly diastereoselective [2 + 2] cycloaddition of a ketene to an enecarbamate, derived from L-pyroglutamic acid.
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http://dx.doi.org/10.1021/ol901919cDOI Listing
October 2009

The superantigen staphylococcal enterotoxin A (SEA) and monoclonal antibody L243 share a common epitope but differ in their ability to induce apoptosis via MHC-II.

Immunobiology 2006 3;211(10):807-14. Epub 2006 Jul 3.

Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany.

Crosslinking of MHC class II (MHC-II) molecules by antibodies or by superantigens (SAg) induces a variety of functional responses in the antigen presenting cell. We were able to allocate K39 as the residue that is essential for binding of antibody L243 to the alpha chain of HLA-DR. K39 is also essential for binding of staphylococcal enterotoxin A (SEA). However, the functional responses of the two ligands differ considerably exemplified by the ability of L243 to induce apoptosis in monocytic cells and in B cells, whereas SEA is unable to activate the apoptosis pathway. Despite the differences in functional responses, both ligands induce cell aggregation in MonoMac-1 cells. The SEA molecule with its two different binding sites associates one MHC alpha chain with one beta chain as opposed to two alpha chains that are brought into close proximity by the two identical antigen binding sites of L243. We therefore conclude that the spatial orientation of dimerized MHC-II and their associated proteins is an important factor for the nature of the transduced signal and consequently the outcome of functional responses.
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http://dx.doi.org/10.1016/j.imbio.2006.05.006DOI Listing
November 2007