FR900359

We used the highly specific Gq/11 inhibitor FR900359 (FR) to elucidate signaling networks that drive proliferation, metabolic reprogramming, and dedifferentiation of UM cells...ssGSEA, unsupervised analysis, and functional studies indicated that mTORC1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) drive metabolic reprogramming in UM cells. Together, these results identified protein kinase signaling networks driven by oncogenic Gq/11 that regulate critical aspects of UM cell biology and provide targets for therapeutic investigation.

YM-254890 (YM) and FR-900359 (FR) have gained much attention due to their ability to inhibit constitutively active Gαq by preventing the release of GDP and thereby inhibiting GDP to GTP exchange. Using pull down techniques to determine if YM promotes an inactive conformation of the PM-restricted GαqQ209L mutants we show that both GαqQ209L and PM-restricted GαqQ209L mutants display increased binding to Gβγ and decreased binding to RGS2 upon YM treatment, suggesting that YM promotes an inactive conformation in these PM-restricted mutants in the same manner as with Gαq WT and GαqQ209L. Our studies suggest that an additional way in which YM inhibits GαqQ209L is by promoting the subcellular redistribution of constitutively active Gαq from the PM to the cytoplasm.

Thereby, the isolation and structure elucidation of novel FR analogs of low abundance is enabled. Further, we explore the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gq/11 mutations and characterize the major metabolite of FR formed in plasma.

In our study we identified the cyclic depsipeptide FR-900359, which is isolated from the evergreen plant Ardisia crenata as an effective inhibitor of constitutively active Gα proteins and their downstream targets. Although our data are preliminary, they might contribute to a future treatment option for patients with metastasized uveal melanoma.