Hot topic: Trends in GPCR drug discovery: new agents, targets and indications

New avenues for GPCR drug discovery have emerged owing to recent advances in receptor pharmacology, technological breakthroughs in structural biology and innovations in biotechnology. A collaboration between the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team) and the Uppsala University have published a detailed analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications [1].

By manually curating CenterWatch’s Drugs in Clinical Trials database and cross-referencing with public sources (such as Drugbank, Pharos and Open Targets), they were able to identify 475 approved drugs that target 108 unique GPCRs (~34% of all FDA-approved drugs) ( Additionally, there are approximately 321 agents that are currently investigated in clinical trials, of which ~20% target 66 potentially novel GPCR targets with no approved drug yet. Of these, 37 are peptide or protein-activated GPCRs.

Other relevant highlights:

  • Based on this data, the authors calculated GPCR-targeted agent success rates of 78%, 39% and 29% for phases I, II and III, respectively — slightly higher than the FDA’s average for all investigated agents.
  • There are early indications that the proportion of GPCR-targeted biologics such as monoclonal antibodies (mAbs) and other recombinant proteins is increasing in early stage clinical trials.
  • There is increasing focus on target selectivity rather than polypharmacology.
  • More allosteric modulators in early stage clinical trials.
  • CNS disorders remain highly represented among the indications of GPCR-targeted agents.
  • Diabetes is highly represented among the GPCR-targeted agents currently in clinical trials.
  • Opportunities are emerging for GPCR-targeted agents in oncology.
  • The GPCR structures are starting to impact drug discovery.

Currently, established GPCR drug targets are used by an average of 10.3 (median = 4) distinct approved agents. This indicates a near saturation of the current target space, and emphasizes the need to identify new druggable receptors in order to develop novel medications. The 224 (56%) non-olfactory GPCRs that are yet to be explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders.

Comments by Alexander Hauser and David Gloriam, University of Copenhagen and GPCRdb.

[1] Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. (2017) Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 16(12):829-842. doi: 10.1038/nrd.2017.178. [PMID:29075003]

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