Researchers at Omeros Corporation, a clinical-stage biopharmaceutical company, have identified compounds that interact with orphan G protein-coupled receptors (GPCRs) P2Y8 and OPN4. P2Y8 (also known as P2RY8) is associated with acute lymphoblastic leukemia (ALL), an aggressive cancer of the white blood cells. ALL is the most common type of malignancy diagnosed in children.

The OPN4 receptor is involved with regulation of circadian rhythms, and could provide a target for drugs to improve alertness and to treat a wide range of sleep disorders ranging from narcolepsy and jet lag to insomnia.

G Protein-Coupled Receptors or GPCRs, which mediate key physiological processes in the body, are one of the most valuable families of drug targets. According to Insight Pharma Reports, GPCR-targeting drugs represent 30 to 40% of marketed pharmaceuticals. Examples include Claritin? (allergy), Zantac? (ulcers and reflux), OxyContin? (pain), Lopressor? (high blood pressure), Imitrex? (migraine headache), Reglan? (nausea) and Abilify? (schizophrenia, bipolar disease and depression) as well as all other antihistamines, opioids, alpha and beta blockers, serotonergics and dopaminergics.

Non-sensory GPCRs
The pharmaceutical industry focuses its GPCR drug discovery efforts mostly on non-sensory GPCRs. Of the 363 total non-sensory GPCRs, approximately 240 have known ligands (molecules that bind the receptors) with nearly half of those targeted either by marketed drugs (46 GPCRs) or by drugs in development (about 70 GPCRs). There are approximately 120 GPCRs with no known ligands, which are termed “orphan GPCRs.” Without a known ligand, drug development for a given receptor is extremely difficult.

Premier drug targets
Reserachers have now unlocked 10 of the 81 Class A orphan GPCRs. GPCRs represent the premier family of drug targets, with more than 30 percent of currently marketed drugs targeting only 46 GPCRs. There are approximately 120 orphan GPCRs, and Omeros, which expects to unlock a large percentage of these for drug development, is initially targeting Class A orphan GPCRs.

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“The P2Y8 and OPN4 receptors are linked to important therapeutic areas that receive significant industry attention,” said Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros. “By identifying compounds that interact with these two orphan receptors, our proprietary screening technology has opened previously closed drug-development pathways for ALL and sleep disorders.”

Ongoing GPCR Program
The company has begun screening orphan GPCRs against its small-molecule chemical libraries using its proprietary, high-throughput cellular redistribution assay (CRA). The reserach team also identified and confirmed sets of compounds that interact selectively with 10 orphan receptors linked to squamous cell carcinoma (GPR87), pancreatic cancer (GPR182),acute lymphoblastic leukemia (P2Y8/P2RY8), metabolic and psychotic disorders(GPR27, GPR85, GPR173), appetite control (GPR101), cognitive disorders (GPR12), sleep disorders (OPN4) and motor control (GPR139). The CRA detects receptor antagonists and agonists. Antagonists comprise the majority of marketed drugs, and all of the compounds identified so far are antagonists.

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