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Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß
The Hedgehog (Hh) signaling pathway is crucial for vertebrate embryonic development, tissue homeostasis and regeneration. Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use. However, the signali...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900058/ https://www.ncbi.nlm.nih.gov/pubmed/31454140 http://dx.doi.org/10.1002/anie.201907632 |
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author | Kremer, Lea Hennes, Elisabeth Brause, Alexandra Ursu, Andrei Robke, Lucas Matsubayashi, Hideaki T. Nihongaki, Yuta Flegel, Jana Mejdrová, Ivana Eickhoff, Jan Baumann, Matthias Nencka, Radim Janning, Petra Kordes, Susanne Schöler, Hans R. Sterneckert, Jared Inoue, Takanari Ziegler, Slava Waldmann, Herbert |
author_facet | Kremer, Lea Hennes, Elisabeth Brause, Alexandra Ursu, Andrei Robke, Lucas Matsubayashi, Hideaki T. Nihongaki, Yuta Flegel, Jana Mejdrová, Ivana Eickhoff, Jan Baumann, Matthias Nencka, Radim Janning, Petra Kordes, Susanne Schöler, Hans R. Sterneckert, Jared Inoue, Takanari Ziegler, Slava Waldmann, Herbert |
author_sort | Kremer, Lea |
collection | PubMed |
description | The Hedgehog (Hh) signaling pathway is crucial for vertebrate embryonic development, tissue homeostasis and regeneration. Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use. However, the signaling cascade is incompletely understood and novel druggable proteins in the pathway are in high demand. We describe the discovery of the Hh‐pathway modulator Pipinib by means of cell‐based screening. Target identification and validation revealed that Pipinib selectively inhibits phosphatidylinositol 4‐kinase IIIβ (PI4KB) and suppresses GLI‐mediated transcription and Hh target gene expression by impairing SMO translocation to the cilium. Therefore, inhibition of PI4KB and, consequently, reduction in phosphatidyl‐4‐phosphate levels may be considered an alternative approach to inhibit SMO function and thus, Hedgehog signaling. |
format | Online Article Text |
id | pubmed-6900058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69000582019-12-20 Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß Kremer, Lea Hennes, Elisabeth Brause, Alexandra Ursu, Andrei Robke, Lucas Matsubayashi, Hideaki T. Nihongaki, Yuta Flegel, Jana Mejdrová, Ivana Eickhoff, Jan Baumann, Matthias Nencka, Radim Janning, Petra Kordes, Susanne Schöler, Hans R. Sterneckert, Jared Inoue, Takanari Ziegler, Slava Waldmann, Herbert Angew Chem Int Ed Engl Research Articles The Hedgehog (Hh) signaling pathway is crucial for vertebrate embryonic development, tissue homeostasis and regeneration. Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use. However, the signaling cascade is incompletely understood and novel druggable proteins in the pathway are in high demand. We describe the discovery of the Hh‐pathway modulator Pipinib by means of cell‐based screening. Target identification and validation revealed that Pipinib selectively inhibits phosphatidylinositol 4‐kinase IIIβ (PI4KB) and suppresses GLI‐mediated transcription and Hh target gene expression by impairing SMO translocation to the cilium. Therefore, inhibition of PI4KB and, consequently, reduction in phosphatidyl‐4‐phosphate levels may be considered an alternative approach to inhibit SMO function and thus, Hedgehog signaling. John Wiley and Sons Inc. 2019-10-04 2019-11-11 /pmc/articles/PMC6900058/ /pubmed/31454140 http://dx.doi.org/10.1002/anie.201907632 Text en © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Kremer, Lea Hennes, Elisabeth Brause, Alexandra Ursu, Andrei Robke, Lucas Matsubayashi, Hideaki T. Nihongaki, Yuta Flegel, Jana Mejdrová, Ivana Eickhoff, Jan Baumann, Matthias Nencka, Radim Janning, Petra Kordes, Susanne Schöler, Hans R. Sterneckert, Jared Inoue, Takanari Ziegler, Slava Waldmann, Herbert Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß |
title | Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß |
title_full | Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß |
title_fullStr | Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß |
title_full_unstemmed | Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß |
title_short | Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß |
title_sort | discovery of the hedgehog pathway inhibitor pipinib that targets pi4kiiiß |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900058/ https://www.ncbi.nlm.nih.gov/pubmed/31454140 http://dx.doi.org/10.1002/anie.201907632 |
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