@article{41c2dc2991ec406f8630f4aecbd23156,
title = "Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIII{\ss}",
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",
author = "Lea Kremer and Elisabeth Hennes and Alexandra Brause and Andrei Ursu and Lucas Robke and Matsubayashi, {Hideaki T.} and Yuta Nihongaki and Jana Flegel and Ivana Mejdrov{\'a} and Jan Eickhoff and Matthias Baumann and Radim Nencka and Petra Janning and Susanne Kordes and Sch{\"o}ler, {Hans R.} and Jared Sterneckert and Takanari Inoue and Slava Ziegler and Herbert Waldmann",
note = "Funding Information: Research at the Max Planck Institute of Molecular Physiology and the Lead Discovery Center was supported by the Max Planck Society and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007–2013)/ERC Grant agreement no. 268309. This study was supported in part by the National Institutes of Health (GM123130 and DK102910 to T.I.). The compound management and screening center (COMAS) Dortmund is acknowledged for performing the primary screening and for IC50 determinations in the osteoblast differentiation assay. We are grateful to Malte Metz and Andreas Brockmeyer (Max Planck Institute of Molecular Physiology) for assistance during MS/MS measurements. A.U. received funding from the IMPRS in Chemical and Molecular Biology (IMPRS-CMB). Hideaki Matsubayashi and Yuta Nihongaki are supported by the Japan Society for the Promotion of Science (JSPS). We thank Gerald R.V. Hammond for providing DNA constructs of P4M PI(4)P sensor and technical advices about P4M live cell imaging. Publisher Copyright: {\textcopyright} 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.",
year = "2019",
month = nov,
day = "11",
doi = "10.1002/anie.201907632",
language = "English",
volume = "58",
pages = "16617--16628",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "46",
}