Hedgehog pathway inhibitors: a patent review (2009 – present)

Abstract

Introduction: The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents.

Areas covered: This review surveys the recent patent literature (2009 – 2012) for Hh pathway inhibitors as treatments for a variety of human malignancies.

Expert opinion: To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling. While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified. Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo. The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling.

Keywords::

• basal cell carcinoma
• cancer
• gli
• hedgehog signaling
• medulloblastoma
• smoothened

Notes

This box summarizes key points contained in the article.