Receptors include several large families of proteins, including nuclear, cell surface membrane, and intracellular. Receptors are typically targeted by one or more ligands and are classified as orphan receptors when a ligand has not been identified. Ligand-receptor complexes are valuable drug targets across various therapeutic areas as they are the first step in intracellular and cell-to-cell communication. Different mechanisms of actions are utilized by drugs targeting ligands and receptors, including competitive inhibition of ligand binding, mimicking ligand function, and inhibition of ligand receptor complex internalization or, in the case of truncated receptors, inhibition of downstream signaling cascades.

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The recent focus on developing therapeutic modalities that harness the immune system to develop new drugs for cancers, and possibly neurodegenerative disease, have identified several key receptors and corresponding ligands in the immune system, including PD-L1, PD1, OX40, GITR, CD markers (CD40, CD27, and CD137), and TIGIT, which are prime drug targets for various diseases including cancers, neurodegenerative diseases, and autoimmune disorders.

The cross-functional discovery teams at Charles River have worked on a wide range of targets in each of these therapeutic areas and are available to progress your nuclear receptor-based project further, whether starting from conventional high-throughput screening or using a structural biology approach.

  • Kynurenic Acid, an Aryl Hydrocarbon Receptor Ligand, Is Elevated in Serum of Zucker Fatty Rats. Integrative Molecular Medicine. 2016, 3(4), 761-763. Full Text.
  • Discovery of Oxa-Sultams as RORc Inverse Agonists Showing Reduced Lipophilicity, Improved Selectivity, and Favorable ADME Properties. Bioorganic & Medicinal Chemistry Letters. 2016, 26(18), 4455-4461. Abstract.
  • Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR. ACS Med. Chem. Lett. 2016, 7, 100-104. Abstract.
  • Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case History. J. Med. Chem. 2015, 58, 8877-8895. Abstract.
  • Identification of N-sulfonyl-tetrahydroquinolines as RORc Inverse Agonists. BioOrg. Med. Chem. Lett. 2015, 25, 4109-4113. Abstract.
  • Discovery of 1-{4-[3-Fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C (RORc or RORγ) Inverse Agonist. J. Med. Chem. 2015, 58, 5308-5322. Abstract.
  • Discovery of imidazo[1,5-a]pyridines and -pyrimidines as Potent and Selective RORc Inverse Agonists. BioOrg. Med. Chem. Lett. 2015, 25, 15, 2907-2912. Abstract.
  • Synthesis and SAR Studies of Analogues of 4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063) as Adenosine A2A Receptor Ligands with Improved Aqueous Solubility. BioOrg. Med. Chem. Lett. 2015, 25, 6, 1212-1216. Abstract.