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

ABSTRACT: Constitutively active G protein α subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in these disorders has yet to be achieved. We found that constitutively active Gα_q in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate-for-guanosine triphosphate (GDP/GTP) exchange to trap constitutively active Gα_q in inactive, GDP-bound Gαβγ heterotrimers. Allosteric inhibition of other Gα subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active Gα_q, FR inhibited second messenger signaling, arrested cell proliferation, reinstated me

SUBMITTER: Onken MD 

PROVIDER: S-EPMC6279241 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature