P9: Molecular conjugates of ligands for the orphan G protein-coupled receptor GPR84

The orphan receptor GPR84, which belongs to the family of rhodopsin-like receptors and couples primarily to Gi/o and G12/13 proteins, is activated by medium chain (hydroxy)fatty acids (C10-C14) at high concentrations, but its cognate ligand is still unknown. Due to its expression in the bone marrow and on immune cells, GPR84 has been proposed as a drug target for immune-related diseases.

Agonists may be applied for immunotherapy of cancer and infections while antagonists could be effective for treating inflammatory diseases, and cancers with high GPR84 expression, e.g. thyroid cancers, some gliomas, and acute myeloid leukemia. The Müller group has established orthogonal functional assays (cAMP-accumulation assays, G protein activation BRET assays and ß-arrestin assays) and optimized different chemical classes of GPR84 agonists and antagonists: 6-(ar)alkylaminouracil derivatives (scaffold I) including the first 3H-labeled agonist radioligand, diindolylmethane derivatives (scaffold II, agonists), and 8-amidochromene-4-ones (scaffold III, antagonists).

Interestingly, the receptor harbours two distinct agonist binding sites. Besides full agonists and antagonists, partial agonists, and biased agonists that preferably activate G protein signaling over ß-arrestin recruitment, have been obtained. The aim of this project is to prepare conjugated compounds based on the developed GPR84 ligands. These are required as research tools and have potential as diagnostic or therapeutic drugs. P9 will be strongly facilitated, and in many cases enabled by the collaborative network of the planned RTG.

Targeted conjugates include (1) conjugates with antibodies (ADCs), nanobodies, and aptamers for drug targeting (collaboration with P8), with macrocyclic drugs (collaboration with P3, P4), peptides (collaboration with P6), and sulfopolyglycosides (collaboration with P5) to obtain dual-active hybrid drugs that attack cancer or bacterial cells and concomitantly activate the immune system; ligands that bind to an intracellular site of GPR84 will be conjugated with E3 ligase-binding compounds to induce chemical knockdown (collaboration with P1); (2) enzymatically or photo-cleavable prodrugs (collaboration with P2) to achieve directed release of the drug with high spatial and temporal resolution; and (3) fluorescent dyes, based on previous development of conjugatable fluorophores by the group, comprising different wavelengths up to the near-infrared range, to be employed as diagnostics, for assay development and for receptor visualization by microscopy or fluorescence-activated cell sorting.