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

Key Points

  • We report an analysis of all drugs and agents currently in clinical trials that act via G protein-coupled receptors (GPCRs) – the most intensively studied drug target family.

  • There are currently 475 drugs (~34% of all drugs approved by the FDA) that act on 108 unique GPCR targets.

  • Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets that do not currently have an approved drug.

  • Biological drugs, allosteric modulators and biased agonists are becoming more frequent in clinical trials.

  • The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although other central nervous system disorders are also highly represented.

  • 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.

  • Further trends in GPCR drug discovery can be analysed in an interactive resource in the GPCRdb database.

Abstract

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

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Figure 1: GPCR drug targets.
Figure 2: Major GPCR families that are established drug targets and targets of agents in clinical trials.
Figure 3: Trends in agent molecule types and modes of action for GPCR-targeted agents.
Figure 4: Trends in the indications of approved GPCR-targeted drugs and agents in clinical trials.
Figure 5: GPCR targets from publication to drugs.
Figure 6: Disease associations for all 398 non-olfactory GPCRs.
Figure 7: Crystallized GPCRs.

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Acknowledgements

The authors thank A. Hersey, S. M. Soisson, V. Chelliah, L. Jahn, K. Harpsøe and M. Shehata for their valuable comments on this work. D.E.G. has received financial support from the European Research Council (DE-ORPHAN 639125) and the Lundbeck Foundation (R163-2013-16327).

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Glossary

Allosteric sites

Sites for ligand binding to a receptor that are remote from the binding site of the physiological agonist (known as the orthosteric site).

Biased agonism

A newly discovered mechanism for potentially reducing drug side effects by using a surrogate agonist to preferentially activate a different intracellular signalling pathway from that of the physiological agonist.

Established GPCR targets

Herein defined as the targets of a drug approved by the US Food and Drug Administration.

Polypharmacology

Ligand binding to multiple targets, all of which contribute to the pharmacological response.

Modes of action

Receptor activity defined as ligand stimulation (agonism), blocking (antagonism), inhibition (inverse agonism), or negative or positive allosteric modulation.

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Hauser, A., Attwood, M., Rask-Andersen, M. et al. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 16, 829–842 (2017). https://doi.org/10.1038/nrd.2017.178

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