Smoothened as a drug target
Smoothened (SMO) is a special GPCR as it couples to G proteins but has also a plethora of other binding partner proteins which, to some extent, define SMO signalling more that G proteins.
SMO does couple to Gi proteins (Qi, Liu et al. 2019) but literature on its ligand-induced G protein activation is limited including opposing data and opinions (Philipp and Caron 2009, Turku, Schihada et al. 2021). Instead, SMO is more often defined as a key protein involved in the Hedgehog signalling pathway (Toftgard 2000). There it interacts with various intracellular binding partners to transduce signals from the extracellular Hedgehog ligands to the nucleus, ultimately regulating gene expression and thus organ development. Activation of SMO leads to inhibition of Gli processing and promotes the accumulation of full-length, transcriptionally active Gli proteins in the nucleus. SMO indirectly regulates Gli proteins by preventing their proteolytic processing. Aberrant SMO signalling is pharmacologically targeted in cancers.
SMO is a representative of quite a small group of GPCRs that are the main target for anti-cancer drugs. SMO has remained de facto non-deorphanized until 2016-2017 albeit officially not classified as an orphan receptor even before that. This receptor is a main target for three small-molecule therapeutics: vismodegib (approved in 2012, basal cell carcinoma), sonidegib (approved in 2015, basal cell carcinoma) and glasdegib (approved in 2018, acute myeloid leukaemia/AML). Interestingly, vismodegib and sonidegib have been approved by FDA before a confirmed deorphanization of the receptor with its cognate ligand cholesterol (Huang, Nedelcu et al. 2016, Luchetti, Sircar et al. 2016, Myers, Neahring et al. 2017). It demonstrates that the deorphanization of a receptor is not a prerequisite for successful therapeutical targeting of a protein.
SMO is a representative of quite a small group of GPCRs that are the main target for anti-cancer drugs. SMO has remained de facto non-deorphanized until 2016-2017 albeit officially not classified as an orphan receptor even before that. This receptor is a main target for three small-molecule therapeutics: vismodegib (approved in 2012, basal cell carcinoma), sonidegib (approved in 2015, basal cell carcinoma) and glasdegib (approved in 2018, acute myeloid leukaemia/AML). Interestingly, vismodegib and sonidegib have been approved by FDA before a confirmed deorphanization of the receptor with its cognate ligand cholesterol (Huang, Nedelcu et al. 2016, Luchetti, Sircar et al. 2016, Myers, Neahring et al. 2017). It demonstrates that the deorphanization of a receptor is not a prerequisite for successful therapeutical targeting of a protein.
Research questions
What is the exact role of the extracellular cysteine-rich domain (CRD) of SMO?
What is the physiological relevance of SMO-mediated Gi signaling?
Project includes
- design of SMO conformational sensors
- development of SMO ligands with novel scaffolds (collaboration with Sandro Cosconati)
- defining SMO in an extended ternary complex model