Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity

Autor: James M. Conley, Karen McGovern, Jeffery L. Kutok, Kerry White, Kerrie Faia, Margaret A. Read, Marisa O. Peluso, Joseph A. Harari, Nigel Whitebread, Thomas T. Tibbitts, Veronica Campbell, Jennifer Proctor
Rok vydání: 2013
Předmět:
Skin Neoplasms
Mouse
Cancer Treatment
lcsh:Medicine
Biochemistry
Receptors
G-Protein-Coupled
chemistry.chemical_compound
Mice
Molecular Cell Biology
Basic Cancer Research
Signaling in Cellular Processes
Membrane Receptor Signaling
Sonic hedgehog
lcsh:Science
Multidisciplinary
biology
Basal Cell Carcinomas
Veratrum Alkaloids
Animal Models
Smoothened Receptor
Hedgehog signaling pathway
Signaling Cascades
Cell biology
Veratrum alkaloid
Oncology
Medicine
Signal transduction
Transmembrane Signaling
Signal Transduction
Research Article
medicine.medical_specialty
Drugs and Devices
Drug Research and Development
Cyclopamine
Malignant Skin Neoplasms
Dermatology
Signaling Pathways
Cell Line
Pancreatic Cancer
Model Organisms
Internal medicine
Gastrointestinal Tumors
medicine
Animals
Humans
Hedgehog Proteins
Cilia
Hedgehog
Biology
lcsh:R
Proteins
Cancers and Neoplasms
Transmembrane Proteins
Endocrinology
chemistry
biology.protein
NIH 3T3 Cells
lcsh:Q
Smoothened
Zdroj: PLoS ONE
PLoS ONE, Vol 9, Iss 3, p e90534 (2014)
ISSN: 1932-6203
Popis: A requisite step for canonical Hedgehog (Hh) pathway activation by Sonic Hedgehog (Shh) ligand is accumulation of Smoothened (Smo) to the primary cilium (PC). Activation of the Hh pathway has been implicated in a broad range of cancers, and several Smo antagonists are being assessed clinically, one of which is approved for the treatment of advanced basal cell carcinoma. Recent reports demonstrate that various Smo antagonists differentially impact Smo localization to the PC while still exerting inhibitory activity. In contrast to other synthetic small molecule Smo antagonists, the natural product cyclopamine binds to and promotes ciliary accumulation of Smo and "primes" cells for Hh pathway hyper-responsiveness after compound withdrawal. We compared the properties of IPI-926, a semi-synthetic cyclopamine analog, to cyclopamine with regard to potency, ciliary Smo accumulation, and Hh pathway activity after compound withdrawal. Like cyclopamine, IPI-926 promoted accumulation of Smo to the PC. However, in contrast to cyclopamine, IPI-926 treatment did not prime cells for hyper-responsiveness to Shh stimulation after compound withdrawal, but instead demonstrated continuous inhibition of signaling. By comparing the levels of drug-induced ciliary Smo accumulation with the degree of Hh pathway activity after compound withdrawal, we propose that a critical threshold of ciliary Smo is necessary for "priming" activity to occur. This "priming" appears achievable with cyclopamine, but not IPI-926, and is cell-line dependent. Additionally, IPI-926 activity was evaluated in a murine tumor xenograft model and a pharmacokinetic/pharmacodynamic relationship was examined to assess for in vivo evidence of Hh pathway hyper-responsiveness. Plasma concentrations of IPI-926 correlated with the degree and duration of Hh pathway suppression, and pathway activity did not exceed baseline levels out to 96 hours post dose. The overall findings suggest that IPI-926 possesses unique biophysical and pharmacological properties that result in Hh pathway inhibition in a manner that differentiates it from cyclopamine.
Databáze: OpenAIRE
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