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Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma
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Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma
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Journal Article
Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma
2019
Overview
Dysregulation of the seven-transmembrane (7TM) receptor Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway contributes to the development of cancers including basal cell carcinoma (BCC) and medulloblastoma (MB). However, SMO-specific antagonists produced mixed results in clinical trials, marked by limited efficacy and high rate of acquired resistance in tumors. Here we discovered that Nilotinib, an approved inhibitor of several kinases, possesses an anti-Hh activity, at clinically achievable concentrations, due to direct binding to SMO and inhibition of SMO signaling. Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting growth of two Hh-dependent MB cell lines. It also reduced tumor growth in subcutaneous MB mouse xenograft model. These results indicate that in addition to its known activity against several tyrosine-kinase-mediated proliferative pathways, Nilotinib is a direct inhibitor of the Hh pathway. The newly discovered extension of Nilotinib's target profile holds promise for the treatment of Hh-dependent cancers.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Analysis
/ Animals
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Cell Proliferation - drug effects
/ Cellular signal transduction
/ Drugs
/ Gliomas
/ Humans
/ Kinases
/ Leukemia
/ Ligands
/ Medicine and Health Sciences
/ Medulloblastoma - drug therapy
/ Mice
/ Pharmacy
/ Phenols (Class of compounds)
/ Proteins
/ Pyrimidines - therapeutic use
/ Research and Analysis Methods
/ Signal Transduction - drug effects
/ Smoothened Receptor - antagonists & inhibitors
/ Smoothened Receptor - chemistry
/ Smoothened Receptor - metabolism
/ Tumors
/ Tyrosine
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