期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 46, 页码 16617-16628出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201907632
关键词
biological activity; Hedgehog signaling; inhibitors; PI4KB
资金
- Max Planck Society
- European Research Council under the European Union [268309]
- National Institutes of Health [GM123130, DK102910]
- IMPRS in Chemical and Molecular Biology (IMPRS-CMB)
- Japan Society for the Promotion of Science (JSPS)
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 III beta (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.
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