The Hedgehog (Hh) signalling pathway is a biochemical pathway involved in embryonic development. Abnormal activation of this pathway in adult tissues, however, promotes tumor growth. Thus, in the search for a treatment for tumors, antagonists of the Hh receptor Smoothened (Smo) have been developed. Most of them, however, have limited efficacy because cancer cells develop resistance to these drugs.
This issue prompted Sarah J. Luchansky, Rishi K. Jain, Novartis Institutes for Biomedical Research, Cambridge, USA, and co-workers to develop novel Hh inhibitors. The researchers synthesized a series of cyclohexyl-methyl aminopyrimidine chemotype compounds (CMAPs; see picture) and demonstrated that they block Hh signalling by activating the orphan receptor GPR39.
The new compounds, thus, act in a Smo-independent manner and may halt the growth of tumors that have acquired a resistance against Smo inhibitors.
- Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39,
Frederic Bassilana, Adam Carlson, Jennifer A DaSilva, Bianka Grosshans, Solange Vidal, Valerie Beck, Barbara Wilmeringwetter, Luis A Llamas, Todd B Showalter, Pascal Rigollier, Aaron Bourret, Arun Ramamurthy, Xu Wu, Fred Harbinski, Samantha Plonsky, Lac Lee, Heinz Ruffner, Paola Grandi, Markus Schirle, Jeremy Jenkins, Andreas W Sailer, Tewis Bouwmeester, Jeffrey A Porter, Vic Myer, Peter M Finan, John A Tallarico, Joseph F Kelleher, Klaus Seuwen, Rishi K Jain, Sarah J Luchansky,
Nat. Chem. Biol. 2014.