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GPR65 inhibition counteracts low pH-dependant immunosuppressive effects on immune cells and displays pronounced anti-tumor activity in mice: Identification of PTT-4256 as a clinical drug candidate.
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PTT-4256 is a first-in-class GPR65 inhibitor that reverses the immuno-suppressive effects of acidic pH in macrophages, activates anti-tumorigenic pathways in the tumor microenvironment and displays single agent anti-tumor efficacy in mice.
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Inhibition of GPR65 counteracts low pH-induced immuno-suppressive polarization of macrophages. In vitro and in vivo characterization of potent, selective and orally bioavailable small molecule GPR65 antagonists.
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Inhibition of acid sensing by GPR65 normalizes gene expression in macrophages, increases immune cell infiltration in tumors, and restrains subcutaneous MC38 growth in mice.
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GPR65 is a critical mediator of low pH-induced immunosuppressive signalling in tumor associated macrophages: human target validation of a novel innate immune checkpoint and small molecule inhibitor drug discovery.
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