Mostrar el registro sencillo del ítem

dc.contributor.author
Arencibia, Jose M.  
dc.contributor.author
Fröhner, Wolfgang  
dc.contributor.author
Krupa, Magdalena  
dc.contributor.author
Pastor Flores, Daniel  
dc.contributor.author
Merker, Piotr  
dc.contributor.author
Oellerich, Thomas  
dc.contributor.author
Neimanis, Sonja  
dc.contributor.author
Schmithals, Christian  
dc.contributor.author
Köberle, Verena  
dc.contributor.author
Süß, Evelyn  
dc.contributor.author
Zeuzem, Stefan  
dc.contributor.author
Stark, Holger  
dc.contributor.author
Piiper, Albrecht  
dc.contributor.author
Odadzic, Dalibor  
dc.contributor.author
Schulze, Jörg O.  
dc.contributor.author
Biondi, Ricardo Miguel  
dc.date.available
2018-09-12T14:23:19Z  
dc.date.issued
2017-02  
dc.identifier.citation
Arencibia, Jose M.; Fröhner, Wolfgang; Krupa, Magdalena; Pastor Flores, Daniel; Merker, Piotr; et al.; An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms; American Chemical Society; ACS Chemical Biology; 12; 2; 2-2017; 564-573  
dc.identifier.issn
1554-8929  
dc.identifier.uri
http://hdl.handle.net/11336/59261  
dc.description.abstract
There is a current and pressing need for improved cancer therapies. The use of small molecule kinase inhibitors and their application in combinatorial regimens represent an approach to personalized targeted cancer therapy. A number of AGC kinases, including atypical Protein Kinase C enzymes (PKCs), are validated drug targets for cancer treatment. Most drug development programs for protein kinases focus on the development of drugs that bind at the ATP-binding site. Alternatively, allosteric drugs have great potential for the development of future innovative drugs. However, the rational development of allosteric drugs poses important challenges because the compounds not only must bind to a given site but also must stabilize forms of the protein with a desired effect at a distant site. Here we describe the development of a new class of compounds targeting a regulatory site (PIF-pocket) present in the kinase domain and provide biochemical and crystallographic data showing that these compounds allosterically inhibit the activity of atypical PKCs. PS432, a representative compound, decreased the rate of proliferation of non-small cell lung cancer cells more potently than aurothiomalate, an atypical PKC inhibitor currently under evaluation in clinical trials, and significantly reduced tumor growth without side effects in a mouse xenograft model. The druglike chemical class provides ample possibilities for the synthesis of derivative compounds, with the potential to allosterically modulate the activity of atypical PKCs and other kinases.  
dc.format
application/pdf  
dc.language.iso
eng  
dc.publisher
American Chemical Society  
dc.rights
info:eu-repo/semantics/openAccess  
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/  
dc.subject
Allosteric Inhibitor  
dc.subject
Pif-Pocket  
dc.subject
Pkc  
dc.subject
Agc Kinase  
dc.subject.classification
Otras Ciencias Biológicas  
dc.subject.classification
Ciencias Biológicas  
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS  
dc.title
An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms  
dc.type
info:eu-repo/semantics/article  
dc.type
info:ar-repo/semantics/artículo  
dc.type
info:eu-repo/semantics/publishedVersion  
dc.date.updated
2018-09-11T14:45:19Z  
dc.journal.volume
12  
dc.journal.number
2  
dc.journal.pagination
564-573  
dc.journal.pais
Estados Unidos  
dc.journal.ciudad
Washington  
dc.description.fil
Fil: Arencibia, Jose M.. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Fröhner, Wolfgang. Universitat Saarland; Alemania  
dc.description.fil
Fil: Krupa, Magdalena. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Pastor Flores, Daniel. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Merker, Piotr. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Oellerich, Thomas. Goethe Universitat Frankfurt; Alemania  
dc.description.fil
Fil: Neimanis, Sonja. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Schmithals, Christian. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Köberle, Verena. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Süß, Evelyn. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Zeuzem, Stefan. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Stark, Holger. Goethe Universitat Frankfurt; Alemania  
dc.description.fil
Fil: Piiper, Albrecht. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemania  
dc.description.fil
Fil: Schulze, Jörg O.. Universitätsklinikum Frankfurt; Alemania  
dc.description.fil
Fil: Biondi, Ricardo Miguel. Universitätsklinikum Frankfurt; Alemania. German Cancer Consortium; Alemania. German Cancer Research Center ; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina  
dc.journal.title
ACS Chemical Biology  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acschembio.6b00827  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.6b00827