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GPCR

G Protein-Coupled Receptors (GPCRs)
G protein-coupled receptors, or GPCRs, comprise one of the largest families of proteins in the genomes of multicellular organisms. It is estimated that there are over 1,000 GPCRs in the human genome, comprising three percent of all human proteins. GPCRs are cell surface membrane proteins involved in mediating both sensory and nonsensory functions. Sensory GPCRs are involved in the perception of light, odors, taste and sexual attractants. Non-sensory GPCRs are involved in metabolism, behavior, reproduction, development, hormonal homeostasis and regulation of the central nervous system. The vast majority of GPCR drug targets are non-sensory. Although GPCRs form a super-family of receptors, individual GPCRs display a high degree of specificity and affinity for the functionally active molecules, or ligands, that bind to a given receptor. Ligands can either activate the receptor (agonists) or inhibit it (antagonists and inverse agonists). When activated by its ligand, the GPCR interacts with intracellular G proteins, resulting in a cascade of signaling events inside the cell that ultimately leads to the particular function linked to the receptor.

The high degree of specificity and affinity associated with GPCRs has contributed to their becoming the largest family of drug targets for therapeutics against human diseases. It is estimated that nearly 40% of all drugs sold worldwide target GPCRs, yet only 46 GPCRs are responsible for this wealth of drugs. Based on available data, we believe that there are 363 human non-sensory GPCRs, of which approximately 120 have no known ligands, and we refer to those receptors as orphan GPCRs. Without a known ligand, there is no template from which medicinal chemistry efforts can be readily initiated nor a means to identify the GPCR’s signaling pathway and, therefore, drugs are very difficult to develop against orphan GPCRs. “Unlocking” these orphan GPCRs by identifying one or more of their respective ligands could lead to the development of drugs that act at these new targets. To our knowledge, despite efforts by others in the biopharmaceutical industry and academic community, Omeros’ technology is the first commercially viable technology capable of identifying ligands of orphan GPCRs in high throughput.

We have developed a proprietary cellular redistribution assay, or CRA, which we use in a high-throughput manner to identify synthetic ligands, including antagonists, agonists and inverse agonists, that bind to and affect the function of orphan GPCRs. We believe that we are the first to possess the capability to conduct high-throughput drug discovery for orphan GPCRs and that there is no other existing high-throughput technology able to “unlock” orphan GPCRs. We have screened Class A orphan GPCRs against our small-molecule chemical libraries using the CRA. In addition to Class A orphan GPCRs, we have also begun screening orphan and non-orphan Class B receptors. Class B GPCRs have large extracellular domains and their natural ligands are generally large peptides, making the development of orally active, small-molecule drugs against these receptors, such as glucagon and parathyroid hormone, a persistent challenge. Despite the fact that oral agents are not available, the current sales for the commercialized Class B GPCR-targeting peptide drugs are large. Our CRA technology finds functionally active small molecules for GPCRs, which we believe could lead to the development of oral medications for many of the Class B GPCRs. Omeros has announced that it has identified and confirmed sets of compounds that interact selectively with the following orphan receptors:

GPCR Metabolic & Cardiovascular Indications GPCROncology Indications
GPR12Obesity, Cognitive Impairments GPR19 Melanoma, Lung Cancer
GPR21 Obesity, Diabetes GPR20 Gastro-Intestinal Stromal Tumors, Acute Myeloid Leukemia
GPR22 Cardiovascular Diseases, Anxiety GPR65 Renal Cell Carcinoma, Ovarian Cancer, Inflammation
GPR25 Arterial Stiffness GPR68 Ovarian Cancer, Prostate Cancer, Osteoporosis
GPR37L1 Hypertension GPR80 Hepatocellular Carcinoma
GPR39 Diabetes GPR87 Squamous Cell Carcinoma
GPR50 Metabolic Disorders GPR150 Ovarian Cancer
GPR61 Eating Disorders GPR161 Breast Cancer, Congenital Cataracts & Birth Defects
GPR82 Appetite, Body Weight GPR174 Regulatory T-Cell Modulation
GPR101 Appetite and Eating Disorders LGR4 Cancer Stem Cells, Bone Diseases
GPR132 Atherosclerosis LGR5 Cancer Stem Cells, Esophageal Adenocarcinoma
GPR146 Dyslipidemia, Diabetes P2Y8 Leukemias, Lymphomas
GPR171 Eating Disorders  
GPR176 Atherosclerosis
SREB1/GPR27 Diabetes, Schizophrenia
GPCRCNS Indications GPCR Miscellaneous Indications
GPR17 Myelin Disorders, Multiple Sclerosis GPR15HIV Enteropathy, Rheumatoid Arthritis
GPR31Anxiety Disorders GPR32 Acute Inflammatory Responses
GPR37 Parkinson’s Disease GPR83 Autoimmune Diseases, PTSD
GPR52Schizophrenia GPR183Osteoporosis and EBV
GPR63Autism CCRL2Rheumatoid Arthritis
GPR78Bipolar Disorder, Schizophrenia LGR6Hair Follicle Stem Cells, Wound Repair
GPR139 Motor Disorders GPCRs with Unknown Indications
GPR151 Cognition, Mood Disorders, Pain
GPR45 GPR182
GPR135 MRGF
GPR141 OPN5
GPR162  
GPR153 Schizophrenia
MAS1 Cognitive Impairments
MRGE Pain
OPN4 Circadian Rhythm, Sleep Disorders
SREB2/GPR85 Schizophrenia, Obesity
SREB3/GPR173 Schizophrenia, Obesity

In parallel, Omeros is executing on its intellectual property strategy to protect each unlocked target through a multipronged approach directed to compound structures, uniquely identified signaling pathways and associated therapeutic indications. Collectively, this approach provides Omeros the opportunity to establish broad and enforceable protection for each unlocked receptor.

Status
We are conducting in vivo preclinical efficacy studies and optimizing compounds for a number of targets including: GPR17, linked to myelin formation; GPR101, linked to appetite and eating disorders; GPR151, linked to schizophrenia and cognition; GPR161, which is associated with triple negative breast cancer; GPR183, linked to osteoporosis and to Epstein-Barr virus infections and related diseases; and GPR174, which appears to be involved in the modulation of regulatory T cells, or “T-regs,” known to be important in autoimmune disease, such as multiple sclerosis, and in cancer and organ transplantation.

Patent Position
As of February 28, 2015, we owned five issued patents and 16 pending patent applications in the U.S., and 43 issued patents and eight pending patent applications in foreign markets, which are directed to previously unknown links between specific molecular targets in the brain and a series of CNS disorders, our cellular redistribution assay and other research tools that are used in our GPCR program and to orphan GPCRs and other GPCRs for which we have identified functionally interacting compounds using our CRA.

Commercial Markets
The GPCR family represents an important source of drug discovery. Of the 363 characterized GPCRs, only about 46 are currently targeted by marketed drugs, yet GPCR-targeted drugs account for 30-40% of all drugs sold worldwide.