Omeros Corporation, a biopharmaceutical company committed to discovering, developing and commercializing products focused on inflammation and disorders of the central nervous system, announced that a compound identified by the company as an antagonist of GPR87, an orphan GPCR recently unlocked for drug development by Omeros and linked to squamous cell carcinoma, potentiates the tumour-killing activity of doxorubicin (Adriamycin), a widely used chemotherapeutic agent. This is the first compound in a series of GPR87 antagonists exclusively identified by Omeros that the company has evaluated in proof-of-concept models. Omeros is currently initiating medicinal-chemistry optimization of the compound.
Adriamycin is a potent chemotherapy drug commonly used to treat leukaemias and Hodgkin's lymphoma, as well as cancers of the breast, lung, stomach, bladder, ovaries and thyroid, soft tissue sarcoma, multiple myeloma, and other types of cancer. While very effective in killing cancer cells, Adriamycin's dosing is limited by its life-threatening damage to heart muscle. The ability to reduce Adriamycin's dosing and its dose-related toxicity, while maintaining its cancer lethality, would be a significant advance in the treatment of multiple types of cancer.
"We are excited by these recent data further confirming that our Cellular Redistribution Assay identifies compounds that interact with orphan GPCRs and affect their function," said Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros. "Despite not yet having optimized this GPR87 antagonist, the compound demonstrates the expected benefit of potentiating tumour-cell killing by Adriamycin. We are eager to evaluate our other GPR87 antagonists, as well as the compounds that we identified as antagonists of GPR85 and GPR101, and look forward to screening the remaining orphans."
Omeros has begun screening orphan GPCRs against its small-molecule chemical libraries using a proprietary, high-throughput assay. Based on the limited screening of libraries to date, Omeros has already identified and confirmed sets of compounds that interact selectively with, and modulate signalling of, three of these orphan receptors linked to cancer (GPR87), obesity (GPR85) and appetite control (GPR101). The assay detects receptor antagonists and agonists. Antagonists comprise the majority of marketed drugs, and all of the compounds identified so far by Omeros are antagonists.
GPCRs, which mediate key physiological processes in the body, are one of the most valuable families of drug targets. Annual worldwide drug sales exceed $700 billion and, according to Insight Pharma Reports, GPCR-targeting drugs represent 30 to 40 percent 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.
The 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 123 GPCRs with no known ligands, which are termed "orphan GPCRs." Without a known ligand, drug development for a given receptor is extremely difficult.
Omeros uses a proprietary high-throughput assay to identify small-molecule agonists and antagonists for orphan GPCRs, unlocking them to drug development. Omeros believes that it is the first to possess the capability to unlock orphan GPCRs in high-throughput, and that currently there is no other comparable technology. The Company believes that there may be more than 60 new drugable targets among the orphan GPCRs. Unlocking these receptors could lead to the development of drugs that act at these new targets. There is a broad range of indications linked to orphan GPCRs including cardiovascular disease, asthma, diabetes, pain, obesity, Alzheimer's disease, Parkinson's disease, multiple sclerosis, schizophrenia, learning and cognitive disorders, autism, osteoporosis, osteoarthritis and several forms of cancer.