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 melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF-driven UM cells. FR promoted UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)–mediated gene silencing, a heretofore unrecognized effector system of constitutively active Gα_q in UM. Constitutively active Gα_q and PRC2 therefore provide therapeutic targets for UM. The development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein–coupled receptors (GPCRs) where targeting a single receptor is ineffective.

组成型活性 G 蛋白 α 亚基会导致癌症、霍乱、斯特奇-韦伯综合征和其他疾病。通过靶向抑制这些疾病中的持续活跃的 Gα 亚基来进行治疗干预尚未实现。我们发现葡萄膜黑色素瘤 (UM) 细胞中的组成型活性 Gα _q受到环缩酚肽 FR900359 (FR) 的抑制。FR 变构抑制鸟苷二磷酸与鸟苷三磷酸 (GDP/GTP) 交换，以将组成型活性 Gα _q捕获在非活性、GDP 结合的 Gαβγ 异三聚体中。其他 Gα 亚基的变构抑制是通过引入 FR 结合位点实现的。_{在由组成型活性 Gα q}驱动的 UM 细胞中，FR 抑制第二信使信号传导、阻止细胞增殖、恢复黑素细胞分化并刺激细胞凋亡。相反，FR 对BRAF驱动的 UM 细胞没有影响。FR 通过重新激活多梳抑制复合物 2 (PRC2) 介导的基因沉默来促进 UM 细胞分化，基因沉默是UM 中迄今为止未被识别的组成性活性 Gα _q的效应系统。因此，组成型活性 Gα _q和 PRC2 为 UM 提供了治疗靶点。开发针对其他 Gα 亚基亚型的 FR 类似物可能会为由组成型活性 Gα 亚基或多个 G 蛋白偶联受体 (GPCR) 驱动的疾病提供新的治疗方法，而针对单一受体是无效的。