G protein-coupled receptors (GPCRs) are the most commonly exploited target in modern medicine; however, they have historically not been targeted in oncology.  Recently, researchers have identified opportunities for targeting GPCRs in oncology, resulting in increased focus by drug developers in using GPCRs as targets in oncology.  This article provides background information on GPCRs as drug targets in general, summarizes why GPCRs are desirable therapeutic targets specifically for oncology, describes the challenges with drug discovery for GPCRs, and provides recent examples of efforts to target GPCRs in oncology.

Prevalence of GPCRs as drug targets

GPCRs have been a major target for drug developers because of their regulation of a wide variety of human physiological processes, including growth, metabolism and homeostasis. According to a recent article in Frontiers in Pharmacology, 30 to 50 percent of marketed drugs are estimated to exert their clinical effects via GPCRs and out of a total of 219 new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA) from 2005 to 2014, 54 (25 percent) target GPCRs. 

Many important categories of routinely used drugs target GPCRs, including angiotensin receptor blockers (ARBs) for hypertension, bronchodilators for asthma, antihistamines for allergy, and H2 blockers for acid reflux.  Indeed, a number of world’s top 10 best-selling drugs, including Advair Diskus (fluticasone propionate and salmeterol), and Abilify (aripiprazole), target GPCRs.

Despite their prevalence in many different areas of medicine as therapeutic targets, GPCRs have historically not been exploited in oncology.  Recent developments, however, have increasingly implicated GPCRs in oncology.  These developments include studies finding that GPCRs control an array of pro-survival signaling (e.g. Ras) and alleviate stress pathways (integrated stress response) in cancer cells. Studies have also found that GPCRs play a role in a microenvironment that is beneficial to tumors. In addition, drugs targeting GPCRs have shown that they can generate their effect without creating toxicity for normal cells.

What are GPCRs?

The GPCR superfamily comprises the largest and most diverse group of surface receptors in mammals. GPCRs are embedded in the cellular membrane and are involved in signal transduction from outside the cell to the cellular interior.  GPCRs regulate physiological responses to a variety of stimuli that amines, peptides, glycoproteins, lipids, nucleotides, and Ca2+ ions. Of the more than 800 members of this superfamily, 350 are known to have ligands (molecules that produce a signal by binding to the GPCR) that include hormones, growth factors and other endogenous molecules.

Cellular signaling by GPCRs generally involves their activation by ligands, which lead to signal transduction to the interior of the cell through changes in their transmembrane structure. The binding of a ligand to a GPCR occurs at an exposed extracellular site on the receptor, which causes a change in the conformation of the receptor protein. This change in protein conformation causes changes in coupling of the receptors to G proteins and other proteins, resulting in several different intracellular effects and signaling cascades.

GPCRs: target for non-oncology drugs

Drugs that targets GPCRs include both agonists and antagonists that are used in the treatment of diseases of nearly every major organ system, including the central nervous system (CNS), cardiovascular, respiratory, metabolic and urogenital systems (Table 1). In addition, 6 out of 20 drugs with the highest global sales target GPCRs (Table 2).

Table 1. Commonly used drugs that target GPCRs

GPCR Class





alfuzosin, terazosin

Benign prostate hyperplasia, high blood pressure


clonidine, bisoprolol, betaxolol

High blood pressure


metoprolol, atenolol

High blood pressure


albuterol, nadolol, penbutolol


Acetylcholine Receptor

M1, M2, M3, M4 and M5


Overactive bladder

M1, M2, M3, M4 and M5





Motion sickness; diarrhea









haloperidol, olanzapine



ropinirole, pramipexole

Parkinson’s disease; Restless legs syndrome



loratadine, cetirizine




Motion sickness


cimetidine, ranitidine


5-HT (serotonin)



Anxiety; depression



Migraine headaches



Type-2 diabetes



fentanyl, codein, meperidine








Prostaglandin E2 receptors


Gastric ulcers


Table 2.  Top selling drugs that target GPCRs


Trade name

Generic name







schizophrenia, bipolar disorders, depression



bipolar disorders, neuro-degenerative disorders









blood pressure

* From IMS Health MIDAS


GPCRs are desirable targets for cancer drugs

GPCRs regulate a broad range of cellular processes that are critical for cancer: cellular proliferation, chemo-resistance, self-renewal, apoptosis, stress signaling, immune evasion, invasion, angiogenesis and metastasis. More specifically, GPCRs regulate the majority of signal transduction pathways that are relevant in cancer cells: EGFR/Ras (proliferation), ATF4/CHOP (cell stress), chemokine (metastasis) and p53 (apoptosis) signaling.

Because GPCRs control and crosstalk with critical pathways, they are frequently hijacked by malignant cells. Systematic analysis of cancer genomes has revealed mutations in GPCRs in about 20 percent of all cancers. Additionally, G proteins are known to be susceptible to genetic alternation, and recent deep sequencing approaches have revealed a high prevalence of hotspot mutations. Although GPCRs are less frequently mutated compared to other oncology pathways and thus have traditionally been ignored in drug discovery efforts for this disease, there is increased recognition that pharmacological engagement of GPCRs provides an opportunity to safely block diverse tumorigenic signals despite challenges in drug discovery.

Challenges with drug discovery for GPCRs

Three main issues have hampered the discovery of drugs that target GPCRs: the high degree of sequence homology in ligand binding sites within GPCRs, the difficulty of protein isolation and crystallization, and challenges with generating antibodies for these receptors.

First, the GPCR superfamily is composed of various subfamilies that differentially regulate signaling pathways and biological processes. However, many subfamilies have overlapping ligands and homologous ligand binding sites, which poses a major challenge in achieving adequate selectivity for ligands.

Second, due to their large size and the majority of the receptors being transmembrane, GPCRs are extremely difficult to stabilize, purify, and crystallize to enable identification of their protein structure. So far, only about 127 crystal structures have been identified for a small subset of GPCRs. This lack of structural information on this receptor class has limited drug discovery approaches that engineer ligands based on the structure of the targeted protein. This limitation may in part explain the under-exploitation of GPCRs in oncology, because rational drug design has been popular in modern oncology following successful targeting of oncogenes enabled by protein structures.

Third, because the majority of these recepetors are buried within the membrane and their ligand binding sites do not lie in the extracellular domains, it has been difficult to identify stable antigens with sufficient integrity, activity and relevant epitopes to generate antibodies.

Owing in part to these challenges, approximately 80 percent of the GPCR family is currently not targeted by approved therapies, despite their relevance in many diseases. Nonetheless, there have been many instances of success, and interest is growing in oncology.  A relevant example is inhibition of the Hedgehog signaling pathway with antagonists of Smoothened (SMO), a GPCR-like seven transmembrane receptor that possesses a structural and functional similarity to classic GPCRs. This inhibition has had success in the treatment of select cancers, such as basal cell carcinoma.

GPCRs have the potential to be a new therapeutic paradigm in oncology

The ability of many drugs on the market to safely engage their targets is a rare feature among therapies that treat life-threatening diseases such as oncology. As the need for new therapeutic targets in oncology becomes increasingly clear and studies continue to implicate these receptors in the pathogenesis and progression of cancer, the potential of this untapped trove of therapeutic targets for oncology is being increasingly recognized. Despite drug discovery challenges, there are promising approaches under development to harness the therapeutic potential of targeting GPCRs in oncology.

For example, methods to stabilize GPCRs have been developed to enable identification of their protein structures and subsequent structure-based drug design.  Using this technology, AZD4635 was created as a small molecule antagonist of the immune checkpoint target A2A that recently entered clinical trials for advanced solid tumors.

In addition, a new chemical class of selective GPCR-targeting small molecules called imipridones has been developed as a novel way to attack cancer. This new class of compounds was developed subsequent to the discovery of the anti-cancer attributes of the first known imipridone, called ONC201, in a phenotypic screen.  This first imipridone was determined to bind the GPCR called dopamine receptor D2 (DRD2), a receptor that plays an important role in neuro-oncology.  In addition, ONC201 has demonstrated signs of efficacy against glioblastoma,  a challenging type of brain cancer, in a Phase II trial at the Dana-Farber Cancer Institute.  (For more details on the role of DRD2 in cancer, see “The Role of DRD2 in Cancer, Drug Discovery & Development, August 23, 2016”.)

Following the discovery of the anti-cancer attributes of ONC201, other imipridones were created using the same chemical core as ONC201.  Studies of these chemical analogs of ONC201 have shown members of this class to be capable of generating anti-cancer effects by engaging distinct GPCRs within the superfamily.  Several imipridones have been shown to engage GPCRs with a high degree of selectivity and have demonstrated potent activity in advanced cancer models.

Because GPCRs couple to a limited array of G proteins within the cell to transduce their signal, there is significant overlap in signaling effects among receptors despite sequence divergence of the receptors themselves. This leads to the therapeutic concept that signaling pathways downstream of GPCRs can be consistently engaged through a variety of distinct receptors. As these receptors have distinct tissue expression patterns, the therapeutic utility of agents that target them for oncology or other diseases may be similarly distinct. In other words, different cancers can be addressed by targeting a given member of the GPCR superfamily that is sufficiently expressed. This tailored approach will require a vast array of selective GPCR-targeting compounds that collectively address the largest superfamily of human surface receptors that are underexploited in oncology.


As the role of GPCRs in oncology gains momentum in the scientific literature and emerging technologies address the aforementioned challenges, this superfamily is poised to yield a new wave of cancer therapies with novel mechanisms of action and exceptional safety profiles.

Varun Prabhu and Rohinton Tarapore, scientists at Oncoceutics, contributed to this article.