Targeting the Hedgehog Pathway: The development of Cyclopamine and the Development of Anti-Cancer Drugs Targeting the Hedgehog Pathway

A.      Gould; S.      Missailidis

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