An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms

Autores
Arencibia, Jose M.; Fröhner, Wolfgang; Krupa, Magdalena; Pastor Flores, Daniel; Merker, Piotr; Oellerich, Thomas; Neimanis, Sonja; Schmithals, Christian; Köberle, Verena; Süß, Evelyn; Zeuzem, Stefan; Stark, Holger; Piiper, Albrecht; Odadzic, Dalibor; Schulze, Jörg O.; Biondi, Ricardo Miguel
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Arencibia, Jose M.. Universitätsklinikum Frankfurt; Alemania
Fil: Fröhner, Wolfgang. Universitat Saarland; Alemania
Fil: Krupa, Magdalena. Universitätsklinikum Frankfurt; Alemania
Fil: Pastor Flores, Daniel. Universitätsklinikum Frankfurt; Alemania
Fil: Merker, Piotr. Universitätsklinikum Frankfurt; Alemania
Fil: Oellerich, Thomas. Goethe Universitat Frankfurt; Alemania
Fil: Neimanis, Sonja. Universitätsklinikum Frankfurt; Alemania
Fil: Schmithals, Christian. Universitätsklinikum Frankfurt; Alemania
Fil: Köberle, Verena. Universitätsklinikum Frankfurt; Alemania
Fil: Süß, Evelyn. Universitätsklinikum Frankfurt; Alemania
Fil: Zeuzem, Stefan. Universitätsklinikum Frankfurt; Alemania
Fil: Stark, Holger. Goethe Universitat Frankfurt; Alemania
Fil: Piiper, Albrecht. Universitätsklinikum Frankfurt; Alemania
Fil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemania
Fil: Schulze, Jörg O.. Universitätsklinikum Frankfurt; Alemania
Fil: Biondi, Ricardo Miguel. Universitätsklinikum Frankfurt; Alemania. German Cancer Consortium; Alemania. German Cancer Research Center ; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Allosteric Inhibitor
Pif-Pocket
Pkc
Agc Kinase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/59261
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/59261
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C IsoformsArencibia, Jose M.Fröhner, WolfgangKrupa, MagdalenaPastor Flores, DanielMerker, PiotrOellerich, ThomasNeimanis, SonjaSchmithals, ChristianKöberle, VerenaSüß, EvelynZeuzem, StefanStark, HolgerPiiper, AlbrechtOdadzic, DaliborSchulze, Jörg O.Biondi, Ricardo MiguelAllosteric InhibitorPif-PocketPkcAgc Kinasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1There 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.Fil: Arencibia, Jose M.. Universitätsklinikum Frankfurt; AlemaniaFil: Fröhner, Wolfgang. Universitat Saarland; AlemaniaFil: Krupa, Magdalena. Universitätsklinikum Frankfurt; AlemaniaFil: Pastor Flores, Daniel. Universitätsklinikum Frankfurt; AlemaniaFil: Merker, Piotr. Universitätsklinikum Frankfurt; AlemaniaFil: Oellerich, Thomas. Goethe Universitat Frankfurt; AlemaniaFil: Neimanis, Sonja. Universitätsklinikum Frankfurt; AlemaniaFil: Schmithals, Christian. Universitätsklinikum Frankfurt; AlemaniaFil: Köberle, Verena. Universitätsklinikum Frankfurt; AlemaniaFil: Süß, Evelyn. Universitätsklinikum Frankfurt; AlemaniaFil: Zeuzem, Stefan. Universitätsklinikum Frankfurt; AlemaniaFil: Stark, Holger. Goethe Universitat Frankfurt; AlemaniaFil: Piiper, Albrecht. Universitätsklinikum Frankfurt; AlemaniaFil: Odadzic, Dalibor. Goethe Universitat Frankfurt; AlemaniaFil: Schulze, Jörg O.. Universitätsklinikum Frankfurt; AlemaniaFil: Biondi, Ricardo Miguel. Universitätsklinikum Frankfurt; Alemania. German Cancer Consortium; Alemania. German Cancer Research Center ; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaAmerican Chemical Society2017-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/59261Arencibia, 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; 564-5731554-8929CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/acschembio.6b00827info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.6b00827info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:56Zoai:ri.conicet.gov.ar:11336/59261instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:50:57.626CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
title An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
spellingShingle An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
Arencibia, Jose M.
Allosteric Inhibitor
Pif-Pocket
Pkc
Agc Kinase
title_short An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
title_full An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
title_fullStr An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
title_full_unstemmed An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
title_sort An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms
dc.creator.none.fl_str_mv Arencibia, Jose M.
Fröhner, Wolfgang
Krupa, Magdalena
Pastor Flores, Daniel
Merker, Piotr
Oellerich, Thomas
Neimanis, Sonja
Schmithals, Christian
Köberle, Verena
Süß, Evelyn
Zeuzem, Stefan
Stark, Holger
Piiper, Albrecht
Odadzic, Dalibor
Schulze, Jörg O.
Biondi, Ricardo Miguel
author Arencibia, Jose M.
author_facet Arencibia, Jose M.
Fröhner, Wolfgang
Krupa, Magdalena
Pastor Flores, Daniel
Merker, Piotr
Oellerich, Thomas
Neimanis, Sonja
Schmithals, Christian
Köberle, Verena
Süß, Evelyn
Zeuzem, Stefan
Stark, Holger
Piiper, Albrecht
Odadzic, Dalibor
Schulze, Jörg O.
Biondi, Ricardo Miguel
author_role author
author2 Fröhner, Wolfgang
Krupa, Magdalena
Pastor Flores, Daniel
Merker, Piotr
Oellerich, Thomas
Neimanis, Sonja
Schmithals, Christian
Köberle, Verena
Süß, Evelyn
Zeuzem, Stefan
Stark, Holger
Piiper, Albrecht
Odadzic, Dalibor
Schulze, Jörg O.
Biondi, Ricardo Miguel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Allosteric Inhibitor
Pif-Pocket
Pkc
Agc Kinase
topic Allosteric Inhibitor
Pif-Pocket
Pkc
Agc Kinase
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Arencibia, Jose M.. Universitätsklinikum Frankfurt; Alemania
Fil: Fröhner, Wolfgang. Universitat Saarland; Alemania
Fil: Krupa, Magdalena. Universitätsklinikum Frankfurt; Alemania
Fil: Pastor Flores, Daniel. Universitätsklinikum Frankfurt; Alemania
Fil: Merker, Piotr. Universitätsklinikum Frankfurt; Alemania
Fil: Oellerich, Thomas. Goethe Universitat Frankfurt; Alemania
Fil: Neimanis, Sonja. Universitätsklinikum Frankfurt; Alemania
Fil: Schmithals, Christian. Universitätsklinikum Frankfurt; Alemania
Fil: Köberle, Verena. Universitätsklinikum Frankfurt; Alemania
Fil: Süß, Evelyn. Universitätsklinikum Frankfurt; Alemania
Fil: Zeuzem, Stefan. Universitätsklinikum Frankfurt; Alemania
Fil: Stark, Holger. Goethe Universitat Frankfurt; Alemania
Fil: Piiper, Albrecht. Universitätsklinikum Frankfurt; Alemania
Fil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemania
Fil: Schulze, Jörg O.. Universitätsklinikum Frankfurt; Alemania
Fil: Biondi, Ricardo Miguel. Universitätsklinikum Frankfurt; Alemania. German Cancer Consortium; Alemania. German Cancer Research Center ; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description 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.
publishDate 2017
dc.date.none.fl_str_mv 2017-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/59261
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
1554-8929
CONICET Digital
CONICET
url http://hdl.handle.net/11336/59261
identifier_str_mv 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
1554-8929
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/acschembio.6b00827
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.6b00827
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269062658260992
score 13.13397

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