| Summary: | Heterotrimeric G-proteins are ubiquitously expressed in several cancers, and they transduce signals from activated G-protein coupled receptors. These proteins have numerous biological functions, and they are becoming interesting target molecules in cancer therapy. Previously, we have shown that heterotrimeric G-protein subunit alphai2 (Gα<sub>i</sub>2) has an essential role in the migration and invasion of prostate cancer cells. Using a structure-based approach, we have synthesized optimized small molecule inhibitors that are able to prevent specifically the activation of the Gα<sub>i</sub>2 subunit, keeping the protein in its inactive GDP-bound state. We observed that two of the compounds (<b>13</b> and <b>14</b>) at 10 μΜ significantly inhibited the migratory behavior of the PC3 and DU145 prostate cancer cell lines. Additionally, compound <b>14</b> at 10 μΜ blocked the activation of Gα<sub>i</sub>2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of Gα<sub>i</sub>2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of Gα<sub>i</sub>2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of Gα<sub>i</sub>2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites.
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