Small Molecule Inhibitors Targeting Gα_i2 Protein Attenuate Migration of Cancer Cells

• Main Authors: Silvia Caggia, Subhasish Tapadar, Bocheng Wu, Smrruthi V. Venugopal, Autumn S. Garrett, Aditi Kumar, Janae S. Stiffend, John S. Davis, Adegboyega K. Oyelere, Shafiq A. Khan
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Cancers
• Subjects: Gα_i2; cell migration; small molecule inhibitors; cancer; invasion
• Online Access: https://www.mdpi.com/2072-6694/12/6/1631

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_i2) 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_i2 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_i2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of Gα_i2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of Gα_i2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of Gα_i2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites.