Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß
Abstract: 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.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß ; volume:58 ; number:46 ; year:2019 ; pages:16617-16628 ; extent:12
Angewandte Chemie / International edition. International edition ; 58, Heft 46 (2019), 16617-16628 (gesamt 12)
- Urheber
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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
- DOI
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10.1002/anie.201907632
- URN
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urn:nbn:de:101:1-2022071209390520995511
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:36 MESZ
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Beteiligte
- 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
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