Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß

0511324 - ÚOCHB 2020 RIV DE eng J - Journal Article
Kremer, L. - Hennes, E. - Brause, A. - Ursu, A. - Robke, L. - Matsubayashi, H. T. - Nihongaki, Y. - Flegel, J. - Mejdrová, Ivana - Eickhoff, J. - Baumann, M. - Nencka, Radim - Janning, P. - Kordes, S. - Schöler, H. R. - Sterneckert, J. - Inoue, T. - Ziegler, S. - Waldmann, H.
Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß.
Angewandte Chemie - International Edition. Roč. 58, č. 46 (2019), s. 16617-16628. ISSN 1433-7851. E-ISSN 1521-3773
Institutional support: RVO:61388963
Keywords : biological activity * Hedgehog signaling * inhibitors * PI4KB
OECD category: Organic chemistry
Impact factor: 12.959, year: 2019
Method of publishing: Open access
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201907632

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.
Permanent Link: http://hdl.handle.net/11104/0301624