Abstract
The Hedgehog signalling pathway plays a critical role in controlling growth, especially during development, but is often over-activated in tumourigenesis. It has recently emerged as an important target for anticancer drugs, with several compounds in clinical trials. This review initially describes the Hedgehog pathway, focussing on the Patched receptor, and the Smoothened GPCR-like protein, as well as discussing the role of Cancer Stem Cells. It subsequently presents the discovery and development of drugs targeting this pathway. The initial focus is on cyclopamine – the first compound discovered that could inhibit the Hedgehog pathway – and selected cyclopamine analogues, including a review of the development of IPI-926. In addition, a number of other compounds are briefly discussed, to give an overview of current therapies in clinical development, and to indicate the possibilities for targeting different parts of the Hedgehog pathway in future. Finally, combination chemotherapy – incorporating a Hedgehog pathway inhibitor as well as another drug – is discussed from the perspective of drug resistance and effects on cancer stem cells.
Keywords: Hedgehog pathway, cancer stem cells, cyclopamine, patched receptor, smoothened protein, cyclopamine analogues, tumourigenesis, signalling, anticancer, GPCR, IPI-926, chemotherapy, drug resistance
Mini-Reviews in Medicinal Chemistry
Title: Targeting the Hedgehog Pathway: The development of Cyclopamine and the Development of Anti-Cancer Drugs Targeting the Hedgehog Pathway
Volume: 11 Issue: 3
Author(s): A. Gould and S. Missailidis
Affiliation:
Keywords: Hedgehog pathway, cancer stem cells, cyclopamine, patched receptor, smoothened protein, cyclopamine analogues, tumourigenesis, signalling, anticancer, GPCR, IPI-926, chemotherapy, drug resistance
Abstract: The Hedgehog signalling pathway plays a critical role in controlling growth, especially during development, but is often over-activated in tumourigenesis. It has recently emerged as an important target for anticancer drugs, with several compounds in clinical trials. This review initially describes the Hedgehog pathway, focussing on the Patched receptor, and the Smoothened GPCR-like protein, as well as discussing the role of Cancer Stem Cells. It subsequently presents the discovery and development of drugs targeting this pathway. The initial focus is on cyclopamine – the first compound discovered that could inhibit the Hedgehog pathway – and selected cyclopamine analogues, including a review of the development of IPI-926. In addition, a number of other compounds are briefly discussed, to give an overview of current therapies in clinical development, and to indicate the possibilities for targeting different parts of the Hedgehog pathway in future. Finally, combination chemotherapy – incorporating a Hedgehog pathway inhibitor as well as another drug – is discussed from the perspective of drug resistance and effects on cancer stem cells.
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Cite this article as:
Gould A. and Missailidis S., Targeting the Hedgehog Pathway: The development of Cyclopamine and the Development of Anti-Cancer Drugs Targeting the Hedgehog Pathway, Mini-Reviews in Medicinal Chemistry 2011; 11 (3) . https://dx.doi.org/10.2174/138955711795049871
DOI https://dx.doi.org/10.2174/138955711795049871 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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