2. Academic Validation
  3. Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß

Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß

  • Angew Chem Int Ed Engl. 2019 Nov 11;58(46):16617-16628. doi: 10.1002/anie.201907632.
Lea Kremer 1,  Elisabeth Hennes 1,  Alexandra Brause 1,  Andrei Ursu 1 2 3,  Lucas Robke 1 2,  Hideaki T Matsubayashi 4,  Yuta Nihongaki 4,  Jana Flegel 1,  Ivana Mejdrová 5,  Jan Eickhoff 6,  Matthias Baumann 6,  Radim Nencka 5,  Petra Janning 1,  Susanne Kordes 6 7,  Hans R Schöler 7 8,  Jared Sterneckert 7 9,  Takanari Inoue 4,  Slava Ziegler 1,  Herbert Waldmann 1 2
Affiliations

Affiliations

  • 1 Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
  • 2 Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Straße 6, 44221, Dortmund, Germany.
  • 3 Current address: Department of Chemistry, The Scripps Research Institute, 110 Scripps Way, Jupiter, FL, 33458, USA.
  • 4 Department of Cell Biology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, 453 Rangos, Baltimore, MD, 21205, USA.
  • 5 Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 16610, Prague 6, Czech Republic.
  • 6 Lead Discovery Center GmbH, Otto-Hahn-Straße 15, 44227, Dortmund, Germany.
  • 7 Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149, Münster, Germany.
  • 8 Medical Faculty, University of Münster, Domagkstr. 3, 48149, Münster, Germany.
  • 9 Technische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden, 01307, Dresden, Germany.
PMID: 31454140 DOI: 10.1002/anie.201907632
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.

Keywords

Hedgehog signaling; PI4KB; biological activity; inhibitors.

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