Coupling metastasis to pH sensing G Protein-coupled receptor-68 through first in class inhibitor identified in an in vivo chemical genetic screen

Acidic milieu is a hallmark of glycolytic metabolism which occurs in cancerous cells. The effect of the acidic environment on cancer progression can be categorized into effects on tumor cell survival, tumor metastasis, inflammatory response, and blood vessels. Yet the underlying signaling and cell biological underpinnings of these phenomena are not well understood. Here, we describe, ogremorphen, a first in class inhibitor of proton-sensing GPCR GPR68. Discovered from a chemical genetic zebrafish screen, ogremorphen perturbed neural crest migration. Furthermore, ogremorphen was shown to inhibit migration in a number of human melanoma lines, which derive from the neural crest. Phenome-wide association study identified a natural variant that is aberrantly active and is associated with metastasis of common cancers. Our study suggests that GPR68 activity is associated with an increased ability for cancer cell migration and contributes to metastasis.