Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß.
Animals
Antineoplastic Agents
/ chemistry
Cell Line
Cell Survival
/ drug effects
Cilia
/ metabolism
Gene Expression
/ drug effects
Hedgehog Proteins
/ antagonists & inhibitors
Humans
Mice
Minor Histocompatibility Antigens
/ genetics
Morpholines
/ pharmacology
Osteogenesis
/ drug effects
Phosphotransferases (Alcohol Group Acceptor)
/ antagonists & inhibitors
Purines
/ pharmacology
RNA Interference
RNA, Small Interfering
/ metabolism
Signal Transduction
/ drug effects
Smoothened Receptor
/ genetics
Structure-Activity Relationship
Thiophenes
/ chemistry
Hedgehog signaling
PI4KB
biological activity
inhibitors
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
11 11 2019
11 11 2019
Historique:
received:
19
06
2019
pubmed:
28
8
2019
medline:
25
9
2020
entrez:
28
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31454140
doi: 10.1002/anie.201907632
pmc: PMC6900058
doi:
Substances chimiques
Antineoplastic Agents
0
Hedgehog Proteins
0
Minor Histocompatibility Antigens
0
Morpholines
0
Purines
0
RNA, Small Interfering
0
Smoothened Receptor
0
Thiophenes
0
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
phosphatidylinositol phosphate 4-kinase
EC 2.7.1.67
purmorphamine
PB12M2F8KY
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
16617-16628Subventions
Organisme : FP7 Ideas: European Research Council
ID : 268309
Pays : International
Organisme : Japan Society for the Promotion of Science
Pays : International
Organisme : Foundation for the National Institutes of Health
ID : GM123130
Pays : International
Organisme : US National Institutes of health grant
ID : DK102910
Pays : International
Informations de copyright
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
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