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Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect

Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to...

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Autores principales: Seo, Minsuh, Kim, Jeong-Do, Neau, David, Sehgal, Inder, Lee, Yong-Hwan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177832/
https://www.ncbi.nlm.nih.gov/pubmed/21957443
http://dx.doi.org/10.1371/journal.pone.0024179
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author Seo, Minsuh
Kim, Jeong-Do
Neau, David
Sehgal, Inder
Lee, Yong-Hwan
author_facet Seo, Minsuh
Kim, Jeong-Do
Neau, David
Sehgal, Inder
Lee, Yong-Hwan
author_sort Seo, Minsuh
collection PubMed
description Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts.
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spelling pubmed-31778322011-09-28 Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect Seo, Minsuh Kim, Jeong-Do Neau, David Sehgal, Inder Lee, Yong-Hwan PLoS One Research Article Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts. Public Library of Science 2011-09-21 /pmc/articles/PMC3177832/ /pubmed/21957443 http://dx.doi.org/10.1371/journal.pone.0024179 Text en Seo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Seo, Minsuh
Kim, Jeong-Do
Neau, David
Sehgal, Inder
Lee, Yong-Hwan
Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect
title Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect
title_full Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect
title_fullStr Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect
title_full_unstemmed Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect
title_short Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect
title_sort structure-based development of small molecule pfkfb3 inhibitors: a framework for potential cancer therapeutic agents targeting the warburg effect
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177832/
https://www.ncbi.nlm.nih.gov/pubmed/21957443
http://dx.doi.org/10.1371/journal.pone.0024179
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