What are the therapeutic implications of GPCR inhibitors?

The G protein-coupled receptors (GPCRs) family is the largest family of membrane proteins in humans and an important target for many drugs. There are more than 800 members in this family, including about 400 olfactory receptors. According to statistics, sales of drugs targeting GPCR account for 27% of the global market. GPCRs have always been one of the important targets for drug discovery because they regulate a wide variety of physiological processes and have targets for drug discovery on the cell surface. Among them, GPCR19 has always been one of the most important targets in the development of new drugs. Moreover, recent research on GPCRs has opened up new strategies for the development of GPCR drugs. For example, allosteric sites that target GPCRs can alter the structure, homeostasis, and function of the receptor, thereby increasing the therapeutic effect. Moreover, an in-depth study of receptor activation mechanisms allows researchers to design agonists that bias activation of specific intracellular signaling pathways, thereby reducing the side effects of activating other signaling pathways. The crystal structures of 44 unique GPCRs and 205 ligand-receptor complexes have been resolved. These findings provide a solid foundation for structure-based drug development and design. Recently, scientists at the University of Copenhagen in Denmark conducted an inventory of all GPCR drugs and GPCR drugs tested in clinical trials.

Major disease indication trends of GPCR inhibitors

Studies have shown that indications for GPCR-targeted drugs are expanding from traditional areas such as hypertension, allergy, anesthesia and schizophrenia to new areas such as AD and obesity. In the past five years, GPCRs have become targets for new indications such as multiple sclerosis (MS), smoking cessation, and short bowel syndrome. Here are some new trends:

1. Central nervous system diseases remain the major disease indications for GPCR modulators

Of the approved GPCR-targeted drugs, 26% of them (at least 79) can be used to treat central nervous system diseases. Since more than 50% of non-olfactory GPCRs are expressed in the cerebral cortex, and neurotransmitter conduction disorders in the GPCR mediator can lead to a variety of neurological and psychological disorders, therefore, neurological diseases will continue to be one of the important indications for GPCR-targeted drugs. Among them, MS, AD, Huntington’s disease and fragile X chromosome syndrome are particularly worthy of attention.

In the field of MS, a drug targeting GPCR has been approved. It is a fingolimod that regulates the function of the S1P1 receptor. In addition, a variety of S1P1 modulators are in clinical phase 2 and phase 3 trials. In addition, drugs targeting cannabinoid receptors and other GPCR targets such as GPR55 are also tested for MS in clinical trials 2 and 3. These advances suggest that more therapies for the treatment of MS through interaction with GPCRs may soon be available.

2. Diabetes is an important indication for the research of GPCR-targeted drugs in the clinical stage

The increase in the market share of drugs for the treatment of metabolic diseases is also reflected in the clinical trials of targeted GPCRs, of which 27 are in the treatment of diabetes and 7 are in the treatment of obesity. As mentioned earlier, peptide drugs targeting the GLP1 receptor have been marketed, but the currently approved drugs are injectable drugs. Oral-type peptide drugs targeting GLP1 receptors and small molecule drugs are in clinical phase 2 and phase 3 test.

In the treatment of diabetes and its complications, there are currently 25 new GPCR targets that are tested in clinical trials. Among the new targets to be noted are GPR119, FFA1 receptor and dopamine D2 receptor.

3. GPCR-targeted drugs in the field of oncology

There are currently 21 anticancer drugs targeting 14 different GPCRs, including GnRH receptor antagonists and SMO receptor inhibitors. In clinical trials, 23 in-situ drugs targeting GPCRs are used to treat cancer, and 7 of them target innovative targets. These innovative targets include chemokine receptors and proteins in the WNT signaling pathway. For example, CCR2 is the target of the monoclonal antibody plozalizumab, which is now in clinical phase 1 trials for the treatment of melanoma. Monoclonal antibodies that target the FZD7 protein in the WNT signaling pathway are used in clinical trials to treat breast and pancreatic cancer.

The future of targeted GPCRs

The proven efficacy of the GPCR family and their important role in diabetes, obesity, AD, and mental illness will continue to be major driving force for GPCR drug discovery. From the current emergence of a large number of new targets and research interests in GPCR structural biology, pharmacology and models, progress in the field of GPCR drug research and development will be further accelerated.

The future of GPCR drug development will be focused on addressing the following key issues:

1. We need appropriate instrumental compounds to determine the biological function of the target and its relevance to the disease. Innovative high-throughput ligand identification methods (such as DNA-encoding libraries) may help discover these compounds.

2. We need improved disease models and genetic engineering systems for target validation. Gene editing techniques such as CRISPR can help with this.

3. Large amounts of compounding and biological data need to be organized into long-term shared databases, such as ChEMBL, Guide to Pharmacology and GPCRdb. These tasks require interdisciplinary collaboration and public-private partnerships in the field of basic and applied GPCR.