UM File # 4782
G protein coupled receptors (GPCRs) are members of a transmembrane receptor family, which play a central role in various signal transduction pathways. As such, they have become key drug targets for a range of therapeutic areas. However, because the pathways in which GPCRs are involved occur widely in physiology, methods to enhance GPCR signaling in a tissue- or pathway-specific manner may provide an attractive approach to enhance currently available GPCR-based therapies. One large protein family, the regulators of G protein signaling (RGS) proteins, strongly modulates GPCR signaling by reducing the amplitude and duration of responses. RGS protein inhibitors have been suggested as novel drug targets to enhance GPCR signaling and/or improve the actions of known GPCR agonist drugs. Until now, there were no biologically active RGS inhibitors.
University of Michigan researchers have developed a class of molecules that selectively inhibits the function of RGS4, which has been recently shown to modulate insulin release from the pancreas and seizure activity in a variety of epilepsy models. One compound, in particular, inhibits RGS4 with nanomolar potency in vitro, low micromolar potency in cells, and also has in vivo activity. These compounds have some activity against other RGS proteins, but with significantly lower potency. These RGS4 inhibitors represent the first examples of small molecules that can inhibit the cellular and in vivo activity of an RGS protein and thus represent unique tool compounds and potential leads for probing cellular and in vivo actions of RGS4.
Applications • RGS4 inhibitor probe • Modulation of GPCR-mediated signaling
Advantages • Acts downstream of receptor activation, and may provide enhanced GPCR signaling in a tissue- or pathway-specific manner • High potency, in a nanomolar range • Can inhibit the cellular and in vivo activity of an RGS protein
Small Molecule Inhibitors of RGS ProteinsTechnology #4782
Questions about this technology? Ask a Technology Manager
- Richard Neubig
- Managed By
- Ed Pagani Associated Director, Health Technologies 734-763-3558
- Patent Protection
- US Patent Pending
- Polyplexed Flow Cytometry Protein Interaction Assay: A Novel High-Throughput Screening Paradigm for RGS Protein Inhibitors J Biomol Screen, Volume 14. Page 610. 2009
- Regulators of G-protein signalling as new central nervous system drug targets. Nat Rev Drug Discov, Volume 1. Page 187. 2002
UM File # 4782