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Selective Small Molecule Inhibitors Of Heterotrimeric G‐Protein Signaling For The Treatment Of Ovarian Cancer
Author(s) -
Bigham Kevin J,
Maher Ellen,
Hazard Starr E,
Blumer Joe B,
Peterson Yuri K
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1010.1
Subject(s) - heterotrimeric g protein , g protein , chemistry , signal transduction , hek 293 cells , g protein coupled receptor , microbiology and biotechnology , gs alpha subunit , cell signaling , small molecule , gq alpha subunit , gi alpha subunit , g beta gamma complex , receptor , pharmacology , cancer research , biochemistry , biology
Overactive signaling at the level of hormone, receptor, or G‐protein can initiate and potentiate cellular transformation and other diseases. We hypothesize that direct inhibition of overactive G‐protein signaling is cytotoxic to ovarian cancers. We describe the development of selective small molecule inhibitors which bind to and stabilize the GDP‐bound form of the Galpha i 1. Initial inhibitors were identified using computational high throughput docking of a 280,000 small molecule database to Galpha i 1‐GDP and counter‐screened against Galpha i 1‐GTP and Galpha q ‐GDP. Nucleotide exchange assays have verified selective G‐protein inhibition. This inhibition was supported by live cell bioluminescence resonance energy transfer (BRET) experiments measuring the interaction of Galpha i 1 with the regulatory protein AGS4 in HEK293 cells. Inhibition of Galpha i 1 but not Galpha q decreased cell viability in SKOV3 ovarian cancer cells. The mechanism of Gi pathway inhibition is also explored. Pharmacologic regulation of both receptor dependent and independent signaling through specific heterotrimeric subunits will provide a unique window into a major signaling axis while providing data and compounds for the treatment of a refractory disease like ovarian cancer.