Significance: Commonly prescribed drugs for congestive heart failure (CHF) include β-adrenergic receptor antagonists or β-blockers. These drugs operate by inhibiting deleterious apoptotic signaling and normalizing inotropic signaling from these receptors. As the β-adrenergic receptor (β₁AR) (dominant subtype in the heart) is systematically down-regulated during CHF while G_i(a G protein that antagonizes contractile signaling) is up-regulated, the ability to selectively control β₂AR signaling becomes an attractive therapeutic approach. It is proposed that biasing receptor interaction with β-arrestins (promoting antiapoptotic signaling and possibly contraction) over G proteins may be therapeutically advantageous for the treatment of CHF. Here, we report a β-arrestin–biased pepducin of the β₂AR that is able to induce cardiomyocyte contractility and antiapoptotic signaling to provide a pharmacological template for next-generation cardiovascular pharmaceuticals.

Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gαq and Gα11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gαq/11 signaling in uveal melanoma cells expressing either mutant Gαq or Gα11. Inhibition of oncogenic Gαq/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gαq/11 mutants may be a potential means of treating uveal melanoma. Implications: Oncogenic Gαq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.