Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß

Lea Kremer, Elisabeth Hennes, Alexandra Brause, Andrei Ursu, Lucas Robke, Hideaki T. Matsubayashi, Yuta Nihongaki, Jana Flegel, Ivana Mejdrová, Jan Eickhoff, Matthias Baumann, Radim Nencka, Petra Janning, Susanne Kordes, Hans R. Schöler, Jared Sterneckert, Takanari Inoue, Slava Ziegler, Herbert Waldmann

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)16617-16628
Number of pages12
JournalAngewandte Chemie - International Edition
Volume58
Issue number46
DOIs
StatePublished - Nov 11 2019

Keywords

  • Hedgehog signaling
  • PI4KB
  • biological activity
  • inhibitors

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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