Discovery of First‐in‐Class Small Molecule Adhesion GPCR Modulators

Abstract

GPR56 (ADGRG1) is a member of a subset of G protein coupled receptors called adhesion GPCRs (AGPCRs). These GPCRs are unique in their possession of an autoproteolytic extracellular domain that cleaves the receptor prior to activation. GPR56 is a model AGPCR that couples to G12/13 family G‐proteins and we recently discovered that it functions as a platelet collagen receptor important for hemostasis. Based on experimental evidence thus far, we believe that GPR56 is a first‐acting collagen sensor for platelets – enabling them to first recognize blood vessel injury and to initiate the platelet program that leads to repair. Despite being biologically relevant in a number of cellular processes and diseases, there is a distinct lack of available small molecule tool compounds for AGPCRs, including GPR56. We conducted a large‐scale high throughput screen to find agonists and antagonists of GPR56. Over 160,000 compounds were screened in conjunction with UM’s Center for Chemical Genomics (CCG) using a cell‐based serum response element (SRE) luciferase gene reporter assay in HEK293T cells. Primary screening yielded ~30 promising candidate full agonists and 8 candidate antagonists that robustly activated or inhibited GPR56 in cell‐based and biochemical assays. These compounds are currently being used in orthogonal platelet activation assays. Knowledge of these receptors is still sparse; the discovery of high affinity agonists and antagonists will be useful probes to explore AGPCR activities in endogenous contexts. These compounds may also serve as leads for the development of GPR56‐targeted pro‐ or anticoagulants.Support or Funding InformationGM120110, NS103946, T32‐GM007315