Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging

  • J Med Chem. 2024 Jul 11;67(13):10875-10890. doi: 10.1021/acs.jmedchem.4c00359.
Yufeng Xiao  1  2 ,  Jing Chen  1  2 ,  Shaoxian Li  1  2 ,  Qing Zhang  1  2  3  4 ,  Yin Liu  5 ,  Linhai Chen  1  2  4 ,  Yadi Sun  1  2  3 ,  Min Gu  1 ,  Xin Xie  1  2  3  5  4 ,  Fajun Nan  1  2  3  4
Affiliations
  • 1. State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 4. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China.
  • 5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
PMID: 38946306 DOI: 10.1021/acs.jmedchem.4c00359
Abstract

GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 Antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.

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