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Review
. 2013 May;34(5):290-8.
doi: 10.1016/j.tips.2013.02.006. Epub 2013 Apr 1.

Molecular Targeting of Gα and Gβγ Subunits: A Potential Approach for Cancer Therapeutics

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Free PMC article
Review

Molecular Targeting of Gα and Gβγ Subunits: A Potential Approach for Cancer Therapeutics

Alan V Smrcka. Trends Pharmacol Sci. .
Free PMC article

Abstract

G-Protein-coupled receptors (GPCRs) signal through G protein α and βγ subunit families to regulate a wide range of physiological and pathophysiological processes. As such, GPCRs are major targets for therapeutic drugs. Downstream targets of GPCRs have also gained interest as a therapeutic approach to complex pathologies involving multiple GPCRs. One such approach involves targeting of the G proteins themselves. Several small molecule Gα and Gβγ modulators have been developed and been tested in various animal models of disease. Here we will discuss the requirements for targeting Gα and Gβγ subunits, the mechanisms of action of currently identified inhibitors, and focus on the potential utility of Gα and Gβγ inhibitors in the treatment of various cancers.

Figures

Figure 1
Figure 1
Structural representations of Gαq and Gβγ with potential sites for small molecule interactions. (a) Gαq bound to YM-254890. The α helical domain is in blue, the Ras-like domain is in red and the linkers connecting the two domains are in green. GDP is in CPK and YM-254890 is in space fill yellow. Rendered from PDB 3AH8. (b) Surface representation of Gβ. In red is the contact surface for the SIGK peptide used in a completion screen for small molecule discovery. Rendered from PDB 1XHM using MolSoft ICM.
Figure 2
Figure 2
Structures of compounds that bind to Gα or Gβγ subunits.

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