Research ArticleDRUG DEVELOPMENT

Targeting nucleotide exchange to inhibit constitutively active G protein α subunits in cancer cells

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Science Signaling  04 Sep 2018:
Vol. 11, Issue 546, eaao6852
DOI: 10.1126/scisignal.aao6852

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Targeting mutant Gα

Activating mutations in G protein α subunits cause various diseases, including some forms of uveal melanoma (UM), an aggressive eye cancer. Onken et al. found that the plant-derived compound FR900359 blocked the growth of Gα-mutant UM cells in culture. FR900359 allosterically inhibited the guanine nucleotide exchange activity of constitutively active Gαq, thereby trapping it in inactive heterotrimers. The loss of Gαq signaling in UM cells induced redifferentiation and cell death. Targeting this compound, if safe, or synthetic derivatives to the uveal tumor tissue may be an effective treatment for patients.