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Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß
Author(s) -
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
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201907632
Subject(s) - smoothened , hedgehog signaling pathway , hedgehog , gli1 , microbiology and biotechnology , biology , gli2 , signal transduction , cilium
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.