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GPCR-Targeted Therapy

Unlocking Therapeutic Opportunities in Difficult-to-drug Targets

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GPCR-Targeted Therapy

G-protein coupled receptors (GPCRs) are important transmembrane proteins superfamily, accounting for 4% of the human genome. The structure of a GPCR typically consists of an extracellular N-terminus linked to seven α-helical transmembrane domains (TMDs) with an intracellular C-terminus. Within the TMD, several motifs are highly conserved with GPCR subfamilies, but the homology between these subfamilies is very limited.

GPCRs play key roles in tissue and cellular physiology, as well as homeostasis. They are implicated in various diseases, including cancer, immune-mediated inflammatory diseases, cardiovascular diseases, infectious diseases, neurological diseases, and metabolic diseases. Approximately 800 GPCRs are known, about 370 of which reveal drug targeting capabilities.

Anti-GPCR Antibody Therapy

Currently, small-molecule drugs are developed to target only a limited proportion of GPCRs. Thus, receptors may be better targeted by antibody-based therapeutics rather than small molecules when given the size of the ligand-binding pocket. The mechanisms of action afforded by antibody-based therapeutics include antagonism (or blocking), agonism (or activating), receptor modulation, as well as other functional effects specifically mediated by the Fc region (such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP)).

In the field of drug development that targets GPCRs, antibodies have revealed unique advantages over small molecule drugs:

  • Superior selectivity and the potential for different mechanisms of action, such as antibody-drug conjugates (ADC), bispecific or multi-specific targeting;
  • Improved pharmacokinetic (PK) & pharmacodynamic (PD) properties due to a more favorable biodistribution, superior half-life with less patient PK variability;
  • Higher selectivity, reduced side effects (especially the central nervous system) and dose regimens.

Project Overviews

Drug discovery targeting GPCRs remains challenging. However, there are a number of startups that use innovative technology platforms to develop small molecules and therapeutic antibodies targeting challenging or previously undruggable GPCRs.

At Protheragen, we help out-license and find co-development opportunities for GPCR-targeted therapeutics in the early stages of development. If you are interested in any of these projects, please contact us for further discussion. We look forward to our collaboration.

Program Target Drug Modality Status Indication
GPCR-targeted Project 001 Thyroid stimulating hormone receptor (TSHR) Monoclonal antibody Preclinical Graves’ disease
GPCR-targeted Project 002 Sphingosine 1-phosphate receptor 1 (S1PR1) Monoclonal antibody Discovery Autoimmune diseases; Inflammation
GPCR-targeted Project 003 R-spondin 3 (RSPO3) Monoclonal antibody Preclinical Cancers
GPCR-targeted Project 004 Parathyroid hormone 1 receptor (PTH1R) Monoclonal antibody Preclinical Hypercalcemia; Hyperparathyroidism
GPCR-targeted Project 005 Prokineticin receptor 1 (PKR1) Monoclonal antibody Preclinical Inflammation
GPCR-targeted Project 006 Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) Monoclonal antibody Preclinical Colorectal cancer; Solid tumors
GPCR-targeted Project 007 Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4); Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) Bispecific antibody Preclinical Solid tumors
GPCR-targeted Project 008 Gastrin releasing peptide receptor (GRPR) Small molecule Preclinical Solid tumors
GPCR-targeted Project 009 G protein-coupled receptor 5D (GPRC5D); CD3 Monoclonal antibody Preclinical Multiple myeloma
GPCR-targeted Project 010 G-protein coupled receptor 20 (GPR20) Antibody-drug conjugate Discovery Gastrointestinal stromal tumor
GPCR-targeted Project 011 G-protein coupled receptor G2A (GRP132) Monoclonal antibody Discovery Pancreatic cancer
GPCR-targeted Project 012 Glucagon-like peptide-1 receptor (GLP-1R) Monoclonal antibody Preclinical Hypoglycemia; Type 2 diabetes mellitus
GPCR-targeted Project 013 Glucose-dependent insulinotropic peptide receptor (GIPR); Glucagon-like peptide-1 receptor (GLP-1R) Monoclonal antibody Preclinical Type 2 diabetes mellitus; Obesity
GPCR-targeted Project 014 Glucagon receptor (GCGR) Monoclonal antibody Preclinical Diabetes; Hyperglycemia
GPCR-targeted Project 015 Frizzled 8 (FZD8) Monoclonal antibody Discovery Solid tumors
GPCR-targeted Project 016 Frizzled 7 (FZD7) Monoclonal antibody Preclinical Cancers
GPCR-targeted Project 017 Frizzled 5 (FZD5) Monoclonal antibody Discovery Ovarian cancer
GPCR-targeted Project 018 Frizzled 4 (FZD4) Monoclonal antibody Preclinical Familial exudative vitreoretinopathy; Cancers
GPCR-targeted Project 019 Frizzled homologue 10 (FZD10) Monoclonal antibody Preclinical Cancers
GPCR-targeted Project 020 Follicle-stimulating hormone receptor (FSHR) Monoclonal antibody Discovery Infertility

Collaboration Opportunity

Protheragen is actively seeking partners to develop these GPCR-targeted therapeutics further. Potential collaboration can be a strategic alliance, licensing, or marketing agreement.

Protheragen’s business is growing rapidly after founded in Ronkonkoma, New York. More offices have been established at different locations across China and the US ever since.

Protheragen Inc.