CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models

Autores
Cabrera, Maia Diana Eliana; Armando, Romina Gabriela; Czarnowski, Ian; Chinestrad, Patricio Manuel; Blanco, Ramiro; Zinni, Maria Alejandra; Gómez, Daniel; Mengual Gómez, Diego Luis; Lorenzano Menna, Pablo
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Pyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attractive target for isoform-specific modulation, offering opportunities for disrupting this equilibrium and altering tumour cell dynamics.This study identifies a novel druggable pocket at the PKM2 dimer interface through conformational analysis. This pocket was exploited in a virtual screening of a large small-molecule library, identifying two promising candidates, C599 and C998. Both compounds exhibited dose-dependent antiproliferative effects in glioblastoma cell lines and induced apoptosis, as evidenced by caspase 3/7 activation. These effects were directly linked to their inhibition of PKM2 enzymatic activity, validating the proposed mechanism of action in their rational design. ADMET studies further highlighted their strong potential as lead PKM2 inhibitors for GBM treatment.Molecular dynamics (MD) simulations and post-MD analyses, including Dynamic Cross-Correlation Maps (DCCM), Probability Density Function (PDF), and Free Energy Landscape (FEL), confirmed the stability of the protein-ligand interactions and highlighted critical residues at the dimer-dimer interface. The Steered MD simulations demonstrated the high affinity of the compounds for PKM2, as evidenced by the requirement of high rupture forces to induce an unbinding event. These results highlight the potential of the compounds as oligomeric modulators of PKM2. These findings position C599 and C998 as promising lead compounds for antitumor applications. Future studies will focus on optimising these candidates and assessing their efficacy in vivo glioblastoma models, reassuring the thoroughness of our research and the potential for further advancements.
Fil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Armando, Romina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Czarnowski, Ian. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Chinestrad, Patricio Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Blanco, Ramiro. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Zinni, Maria Alejandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Gómez, Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Mengual Gómez, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Lorenzano Menna, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Materia
PKM2
Pharmacological inhibitors
Docking based virtual screening
Molecular dynamics
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/275838
Acceder
id CONICETDig_f60f6560948223c965d8021a5ff849c7
oai_identifier_str oai:ri.conicet.gov.ar:11336/275838
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma modelsCabrera, Maia Diana ElianaArmando, Romina GabrielaCzarnowski, IanChinestrad, Patricio ManuelBlanco, RamiroZinni, Maria AlejandraGómez, DanielMengual Gómez, Diego LuisLorenzano Menna, PabloPKM2Pharmacological inhibitorsDocking based virtual screeningMolecular dynamicshttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Pyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attractive target for isoform-specific modulation, offering opportunities for disrupting this equilibrium and altering tumour cell dynamics.This study identifies a novel druggable pocket at the PKM2 dimer interface through conformational analysis. This pocket was exploited in a virtual screening of a large small-molecule library, identifying two promising candidates, C599 and C998. Both compounds exhibited dose-dependent antiproliferative effects in glioblastoma cell lines and induced apoptosis, as evidenced by caspase 3/7 activation. These effects were directly linked to their inhibition of PKM2 enzymatic activity, validating the proposed mechanism of action in their rational design. ADMET studies further highlighted their strong potential as lead PKM2 inhibitors for GBM treatment.Molecular dynamics (MD) simulations and post-MD analyses, including Dynamic Cross-Correlation Maps (DCCM), Probability Density Function (PDF), and Free Energy Landscape (FEL), confirmed the stability of the protein-ligand interactions and highlighted critical residues at the dimer-dimer interface. The Steered MD simulations demonstrated the high affinity of the compounds for PKM2, as evidenced by the requirement of high rupture forces to induce an unbinding event. These results highlight the potential of the compounds as oligomeric modulators of PKM2. These findings position C599 and C998 as promising lead compounds for antitumor applications. Future studies will focus on optimising these candidates and assessing their efficacy in vivo glioblastoma models, reassuring the thoroughness of our research and the potential for further advancements.Fil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Armando, Romina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Czarnowski, Ian. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Chinestrad, Patricio Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Blanco, Ramiro. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Zinni, Maria Alejandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Gómez, Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Mengual Gómez, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Lorenzano Menna, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaElsevier2025-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/275838Cabrera, Maia Diana Eliana; Armando, Romina Gabriela; Czarnowski, Ian; Chinestrad, Patricio Manuel; Blanco, Ramiro; et al.; CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models; Elsevier; Heliyon; 11; 3; 2-2025; 1-192405-8440CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2405844025006188info:eu-repo/semantics/altIdentifier/doi/10.1016/j.heliyon.2025.e42238info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T13:44:39Zoai:ri.conicet.gov.ar:11336/275838instacron: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:34982025-12-23 13:44:39.868CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
title CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
spellingShingle CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
Cabrera, Maia Diana Eliana
PKM2
Pharmacological inhibitors
Docking based virtual screening
Molecular dynamics
title_short CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
title_full CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
title_fullStr CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
title_full_unstemmed CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
title_sort CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models
dc.creator.none.fl_str_mv Cabrera, Maia Diana Eliana
Armando, Romina Gabriela
Czarnowski, Ian
Chinestrad, Patricio Manuel
Blanco, Ramiro
Zinni, Maria Alejandra
Gómez, Daniel
Mengual Gómez, Diego Luis
Lorenzano Menna, Pablo
author Cabrera, Maia Diana Eliana
author_facet Cabrera, Maia Diana Eliana
Armando, Romina Gabriela
Czarnowski, Ian
Chinestrad, Patricio Manuel
Blanco, Ramiro
Zinni, Maria Alejandra
Gómez, Daniel
Mengual Gómez, Diego Luis
Lorenzano Menna, Pablo
author_role author
author2 Armando, Romina Gabriela
Czarnowski, Ian
Chinestrad, Patricio Manuel
Blanco, Ramiro
Zinni, Maria Alejandra
Gómez, Daniel
Mengual Gómez, Diego Luis
Lorenzano Menna, Pablo
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PKM2
Pharmacological inhibitors
Docking based virtual screening
Molecular dynamics
topic PKM2
Pharmacological inhibitors
Docking based virtual screening
Molecular dynamics
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Pyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attractive target for isoform-specific modulation, offering opportunities for disrupting this equilibrium and altering tumour cell dynamics.This study identifies a novel druggable pocket at the PKM2 dimer interface through conformational analysis. This pocket was exploited in a virtual screening of a large small-molecule library, identifying two promising candidates, C599 and C998. Both compounds exhibited dose-dependent antiproliferative effects in glioblastoma cell lines and induced apoptosis, as evidenced by caspase 3/7 activation. These effects were directly linked to their inhibition of PKM2 enzymatic activity, validating the proposed mechanism of action in their rational design. ADMET studies further highlighted their strong potential as lead PKM2 inhibitors for GBM treatment.Molecular dynamics (MD) simulations and post-MD analyses, including Dynamic Cross-Correlation Maps (DCCM), Probability Density Function (PDF), and Free Energy Landscape (FEL), confirmed the stability of the protein-ligand interactions and highlighted critical residues at the dimer-dimer interface. The Steered MD simulations demonstrated the high affinity of the compounds for PKM2, as evidenced by the requirement of high rupture forces to induce an unbinding event. These results highlight the potential of the compounds as oligomeric modulators of PKM2. These findings position C599 and C998 as promising lead compounds for antitumor applications. Future studies will focus on optimising these candidates and assessing their efficacy in vivo glioblastoma models, reassuring the thoroughness of our research and the potential for further advancements.
Fil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Armando, Romina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Czarnowski, Ian. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Chinestrad, Patricio Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Blanco, Ramiro. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Zinni, Maria Alejandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Gómez, Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Mengual Gómez, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Lorenzano Menna, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
description Pyruvate kinase isoform M2 (PKM2) is a multifunctional enzyme capable of transitioning between monomeric, dimeric, and tetrameric states, with its oligomeric equilibrium playing a pivotal role in tumour progression and survival. The unique exon ten at the dimer-dimer interface represents an attractive target for isoform-specific modulation, offering opportunities for disrupting this equilibrium and altering tumour cell dynamics.This study identifies a novel druggable pocket at the PKM2 dimer interface through conformational analysis. This pocket was exploited in a virtual screening of a large small-molecule library, identifying two promising candidates, C599 and C998. Both compounds exhibited dose-dependent antiproliferative effects in glioblastoma cell lines and induced apoptosis, as evidenced by caspase 3/7 activation. These effects were directly linked to their inhibition of PKM2 enzymatic activity, validating the proposed mechanism of action in their rational design. ADMET studies further highlighted their strong potential as lead PKM2 inhibitors for GBM treatment.Molecular dynamics (MD) simulations and post-MD analyses, including Dynamic Cross-Correlation Maps (DCCM), Probability Density Function (PDF), and Free Energy Landscape (FEL), confirmed the stability of the protein-ligand interactions and highlighted critical residues at the dimer-dimer interface. The Steered MD simulations demonstrated the high affinity of the compounds for PKM2, as evidenced by the requirement of high rupture forces to induce an unbinding event. These results highlight the potential of the compounds as oligomeric modulators of PKM2. These findings position C599 and C998 as promising lead compounds for antitumor applications. Future studies will focus on optimising these candidates and assessing their efficacy in vivo glioblastoma models, reassuring the thoroughness of our research and the potential for further advancements.
publishDate 2025
dc.date.none.fl_str_mv 2025-02
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/11336/275838
Cabrera, Maia Diana Eliana; Armando, Romina Gabriela; Czarnowski, Ian; Chinestrad, Patricio Manuel; Blanco, Ramiro; et al.; CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models; Elsevier; Heliyon; 11; 3; 2-2025; 1-19
2405-8440
CONICET Digital
CONICET
url http://hdl.handle.net/11336/275838
identifier_str_mv Cabrera, Maia Diana Eliana; Armando, Romina Gabriela; Czarnowski, Ian; Chinestrad, Patricio Manuel; Blanco, Ramiro; et al.; CADD-based discovery of novel oligomeric modulators of PKM2 with antitumor activity in aggressive human glioblastoma models; Elsevier; Heliyon; 11; 3; 2-2025; 1-19
2405-8440
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2405844025006188
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.heliyon.2025.e42238
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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_ 1852335359807979520
score 12.952241

Publicaciones similares