Mechanistic insights and target identification of novel Gli1-selective Hedgehog pathway antagonists

Summary

Hedgehog (Hh) signaling is vital for embryonic development and postnatal stem cell renewal, tissue repair, and regeneration. Uncontrolled activation of the pathway by a variety of mechanisms is the underlying cause for multiple forms of cancers. Small-molecule inhibitors of specific pathway components can be used as therapeutic intervention for Hh pathway-dependent types of cancer. The aim of the work described in this proposal is to elucidate the cellular target and mechanism of action of a recently discovered class of Hh pathway antagonists, glimidazoles. This class acts downstream of Smo, at the level of Gli1, a potent oncogene that is nonessential for normal physiology. Gli1 antagonists are therefore not likely to compromise pediatric health and normal development when used as anti-cancer treatment. This project combines organic synthetic, biochemical, and genetic approaches to identify the glimidazole target, which will then be assessed for its physiological role in Hh pathway regulation. The results of this work will provide fundamental insights into unexplored aspects of the Hh signaling pathway and create novel opportunities for the development of anti-cancer therapeutics that can be used in children as well as adults.

Output

Scientific article

Details

Project number

680-50-1304

Main applicant

Dr. S. Hoogendoorn

Affiliated with

Universiteit Leiden, Faculteit der Wiskunde en Natuurwetenschappen, Organische chemie

Team members

Dr. S. Hoogendoorn

Duration

01/02/2014 to 29/02/2016