GPCRs: The Most Potential Drug Targets

The most extensively researched therapeutic targets are G protein-coupled receptors (GPCRs), partly because of their important role in human pathophysiology and their pharmacological tractability. 107 distinct GPCR targets are acted upon by 481 medicines or approximately 34% of all FDA-approved medications. The number of biological medicines, allosteric modulators, and biased agonists has increased. There are presently over 320 compounds in clinical studies, of which 36% target 64 potentially new GPCR sites without an authorized medication. While other illnesses of the central nervous system continue to be heavily represented, diabetes, obesity, and Alzheimer's disease now account for the majority of disease indications for GPCR modulators. There is a vast untapped therapeutic potential for the 227 (57%) non-olfactory GPCRs that have not yet been investigated in clinical trials, notably in genetic and immune system illnesses.

Established and clinical trial GPCR drug targets. Fig.1 Established and clinical trial GPCR drug targets. (Hauser, 2017)

Orphan Receptors Enter Clinical Trials

Several orphan GPCRs that lack endogenous ligands are now being tested in clinical studies. The leucine-rich repeat-containing G protein-coupled receptors 4 and 5 (LGR4/5) for the treatment of gastrointestinal disease, the orphan GPCR GPR35 for the treatment of an allergic inflammatory condition, the orphan GPCR GPR55 as an antispasmodic target, the orphan GPCR proto-oncogene Mas (MAS) for the treatment of thrombocytopenia, and the orphan GPCR GPR84 for the treatment of ulcerative colitis are just This suggests that despite our inadequate understanding of the endogenous ligand and/or signaling system, the drug discovery process can continue to proceed and even advance.

Trends in Disease Indications

The list of indications for GPCR-targeted drugs is extending beyond formerly popular conditions including hypertension, allergies, analgesia, schizophrenia, and depression to more recent conditions like Alzheimer's disease and obesity. GPCRs have also been targeted for new indications over the past five years, including multiple sclerosis, quitting smoking, short bowel syndrome, and hypocalcemia.

  • Central nervous system disorders

The central nervous system (CNS) disorders account for 130 (27 percent) of all approved GPCR-targeted medicines when the indications of these medications are grouped into higher-level disease categories. Furthermore, there is still a lot of interest as evidenced by the fact that 137 GPCR-targeting drugs are undergoing clinical trials for CNS purposes. More than half of all non-olfactory GPCRs are expressed in the cerebral cortex, according to studies on the mouse brain and analysis of receptor baseline expression from the human protein atlas. Multiple neurological and psychiatric illnesses can result from malfunctions in GPCR-mediated neurotransmission, making these receptors interesting therapeutic targets.

  • Diabetes

The significant number of GPCR-targeted drugs in clinical trials for diabetes and obesity-27 and seven agents, respectively-reflect the expanding market share of medications for metabolic diseases. These compounds represent less than 10% of all agents in current studies. Exenatide, a GLP-1 receptor agonist (also known as an incretin mimic), was the first GPCR-targeted medication for type 2 diabetes to receive approval. Other peptidic GLP1 receptor agonists that have received approval recently include liraglutide, lixisenatide, dulaglutide, and albiglutide. They are all designed as injectable medications; however, their durations of action vary.

  • Opportunities emerging for GPCR-targeted agents in oncology

Currently, 15 different GPCRs mediate the effects of 21 authorized medicines having antineoplastic indications. Among them are vismodegib, a smoothened (SMO) receptor inhibitor for the treatment of basal-cell carcinoma, and degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist licensed for patients with advanced prostate cancer. Sonidegib, another SMO receptor inhibitor, received FDA approval as a GPCR-targeted drug in cancer in 2015 for the treatment of basal cell carcinoma.

  • Repurposing of existing GPCR-targeted drugs for new indications

The time and cost required to bring a treatment to market can be decreased by repurposing existing medications for new uses. The fact that 160 (33 percent) of the approved GPCR-targeted medications have more than one indication and that the average number of indications is 1.5 shows that many of these treatments are already utilized for multiple indications. Similar to the number of licensed medications, clinical trial agents often have the same number of indications.

As evidenced by the large number of novel therapeutic targets and the increased scientific interest in GPCR structural biology, pharmacology, and modeling, GPCR drug discovery has experienced a surge. The GPCR protein family's shown druggability and the significance of GPCRs in diseases like diabetes, obesity, Alzheimer's disease, and psychiatric disorders serve as powerful motivators for ongoing drug discovery and development activities in this sector. Creative Biolabs offers GPCR drug discovery service to advance our global clients’ projects.


  1. Hauser, A. S.; et al. Trends in GPCR drug discovery: new agents, targets and indications. Nature reviews Drug discovery. 2017, 16(12): 829-842.
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