Year: 2019
Type: 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.
Authors: 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
Institutions: Max Planck Institute of Molecular Physiology, Scripps Research Institute, TU Dortmund University, Johns Hopkins University, Johns Hopkins Medicine, Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry, Lead Discovery Center (Germany), Max Planck Institute for Molecular Biomedicine, University of Münster, Center for Regenerative Therapies Dresden, Technische Universität Dresden
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: Foundation for the National Institutes of Health, Max-Planck-Gesellschaft, International Max Planck Research School for Advanced Methods in Process and Systems Engineering, National Institutes of Health, Japan Society for the Promotion of Science, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, FP7 Ideas: European Research Council
OpenAlex ID: W2970833768