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

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.

Figure 1. Established and clinical trial GPCR drug targets.

Established targets have approved drugs as defined in the Drugs@FDA database, and targets of agents in clinical trials were collected from manual annotation of CenterWatch’s Drugs in Clinical Trials database, OpenTargets, Drugbank, Pharos and company press releases. a | Established (red) and phase I-III (shades of green) targets across the GPCR classes, ligand types and receptor families (from center to outer ring). The sizes of the circles represent the number of agents. An interactive tree is available at http://www.gpcrdb.org/drugs/drugmapping. b | There are 398 non-olfactory GPCRs, of which 107 have drugs approved (red), 64 have agents that have reached clinical trials but have not yet been approved (green), and 227 are yet to be targeted by agents in clinical trials (grey). The 107 established GPCR drug targets (left doughnut) are primarily aminergic and opioid receptors, whereas most targets of agents that have at least reached clinical trials are types of peptide receptor (right doughnut).

Figure 2. Trends in agent molecule types and modes of action for GPCR-targeted agents.

a | Most GCPR-targeted agents in clinical trials are still small molecules, but the earlier phases display increasing shares of peptides, monoclonal antibodies, other recombinant proteins and other agent types. Discontinued trials show the same trend, and similar proportions of small molecule versus biologics, suggesting that their overall attrition rates are also similar. b | Modes of action are predominantly agonist and antagonists, but more positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) have entered phases I and II, respectively. Discontinued trials demonstrate similar proportions of agonists and antagonists, suggesting similar rates of attrition. Modes of action had not been reported for 67 agents, which were excluded. c | Target selectivity is increasing (that is, polypharmacology is decreasing) in ongoing clinical trials of GPCR-targeted agents. For panels a, b and c, the data from clinicaltrials.gov was aggregated for agents in trial (completed: 156, recruiting: 91, ongoing: 41, not open yet: 18 and suspended: 3) or discontinued (discontinued: 205, terminated: 14, withdrawn: 4).

Figure 3. Trends in the indications of approved GPCR-targeted drugs and agents in clinical trials.

a | The largest number (>40) of approved agents (x-axis) are seen for analgesics, allergy and hypertension; whereas among agents in trials (y-axis) the highest listings (>20) are diabetes and neoplasms. The diagonal arrow and colour gradient from red to green highlights the most established and novel indications, calculated as the ratio of approved and in-trial agents, respectively. Alzheimer’s disease and obesity are the areas with the highest ratio of in-trial agents to approved agents, followed by asthma, diabetes, Parkinson’s disease and neoplasms. Data was manually annotated from the CenterWatch database and public resources. b | The number of indications is similar for approved drugs and currently investigated agents. c | 51 (11%) of the approved GPCR drugs are currently being repurposed for other indications, and account for 9%, 7% and 14% of the agents in phases I, II and III, respectively. For panels b and c, the data from clinicaltrials.gov was aggregated for agents in trial (completed: 156, recruiting: 91, ongoing: 41, not open yet: 18 and suspended: 3) or discontinued (discontinued: 205, terminated: 14, withdrawn: 4).

Figure 4. GPCR targets from publication to drugs.

For each non-olfactory GPCR (y-axis), the panels show the number of: a | publications (in PubMed), b | crystal structures (in the Protein Data Bank), c | ligands (in ChEMBL), d | patents (filed through the World Intellectual Property Organization after 2014), and e | drugs on the market and in clinical trials. GPCRs are sorted by the number of publications. This comparison reveals a highly disproportionate knowledge landscape for GPCR research and drug discovery, indicating an unutilized expansion potential.

Figure 5. Disease associations of all (398) non-olfactory GPCRs.

Disease associations for receptors not yet targeted (grey), with an agent in trial (green) and approved (red) drug. The 227 non-targeted GPCRs are associated with a wide range (18/20) of diseases demonstrating a broad untapped therapeutic potential. Overall, the largest number of GPCR targets (77, numbers to the right) are observed for genetic and nervous system disorders. Disease associations have been agglomerated from the Open Targets platform by combining association scores above a value of 0.5 (at least half of the highest association confidence). The association score summarises the strength of evidence from each data source (genome-wide association studies, genetic variants, expression data and animal models); see Further information. Three ontology terms measurement, phenotype, and biological process, were excluded as they cannot be interpreted as a distinct category. It should be noted that receptors can be associated with multiple systems.

Figure 6. Crystallized receptors.

a | No. of agents in each clinical phase for each crystallized receptor sorted by year. b | Classification tree of all crystallised GPCRs. c | Percentage of each receptor type among all crystallised receptors. Figures b-c were collected from GPCRdb (http://gpcrdb.org/structure/statistics).