MENLO PARK, CA, United States
MENLO PARK, CA, United States

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Punnonen J.,Stategics, Inc. | Miller J.L.,Stategics, Inc. | Collier T.J.,Michigan State University | Spencer J.R.,Stategics, Inc.
Current Topics in Medicinal Chemistry | Year: 2015

Parkinson’s disease (PD) is a neurodegenerative disease affecting more than a million people in the USA alone. While there are effective symptomatic treatments for PD, there is an urgent need for new therapies that slow or halt the progressive death of dopaminergic neurons. Significant progress has been made in understanding the pathophysiology of PD, which has substantially facilitated the discovery efforts to identify novel drugs. The tissue-protective erythropoietin (EPO) receptor, EPOR/CD131, has emerged as one promising target for disease-modifying therapies. Recombinant human EPO (rhEPO), several variants of EPO, EPO-mimetic peptides, cell-based therapies using cells incubated with or expressing EPO, gene therapy vectors encoding EPO, and small molecule EPO mimetic compounds all show potential as therapeutic candidates. Agonists of the EPOR/CD131 receptor demonstrate potent anti-apoptotic, antioxidant, and anti-inflammatory effects and protect neurons, including dopaminergic neurons, from diverse insults in vitro and in vivo. When delivered directly to the striatum, rhEPO protects dopaminergic neurons in animal models of PD. Early-stage clinical trials testing systemic rhEPO have provided encouraging results, while additional controlled studies are required to fully assess the potential of the treatment. Poor CNS availability of proteins and challenges related to invasive delivery limit delivery of EPO protein. Several variants of EPO and small molecule agonists of the EPO receptors are making progress in preclinical studies and may offer solutions to these challenges. While EPO was initially discovered as the primary modulator of erythropoiesis, the discovery and characterization of the tissue-protective EPOR/CD131 receptor offer an opportunity to selectively target the neuroprotective receptor as an approach to identify disease-modifying treatments for PD. © 2015 Bentham Science Publishers.


Miller J.L.,Stategics, Inc. | Church T.J.,Stategics, Inc. | Leonoudakis D.,Stategics, Inc. | Lariosa-Willingham K.,Stategics, Inc. | And 4 more authors.
Molecular Pharmacology | Year: 2015

Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy. Here, we describe the discovery and characterization of the nonpeptidyl compound STS-E412 (2-[2-(4-chlorophenoxy) ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine), which selectively activates the tissue-protective EPO receptor, comprising an EPO receptor subunit (EPOR) and the common β-chain (CD131). STS-E412 triggered EPO receptor phosphorylation in human neuronal cells. STS-E412 also increased phosphorylation of EPOR, CD131, and the EPO-associated signaling molecules JAK2 and AKT in HEK293 transfectants expressing EPOR and CD131. At low nanomolar concentrations, STS-E412 provided EPO-like cytoprotective effects in primary neuronal cells and renal proximal tubular epithelial cells. The receptor selectivity of STS-E412 was confirmed by a lack of phosphorylation of the EPOR/EPOR homodimer, lack of activity in off-target selectivity screening, and lack of functional effects in erythroleukemia cell line TF-1 and CD34+ progenitor cells. Permeability through artificial membranes and Caco-2 cell monolayers in vitro and penetrance across the blood-brain barrier in vivo suggest potential for central nervous system availability of the compound. To our knowledge, STS-E412 is the first nonpeptidyl, selective activator of the tissue-protective EPOR/CD131 receptor. Further evaluation of the potential of STS-E412 in central nervous system diseases and organ protection is warranted. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Disclosed herein are erythropoietin-mimetic compounds of Formula I, which modulate the survival, function, or differentiation of, for example, kidney cells, neurons, erythroid cells, or other erythropoietin-responsive cells. The present invention also relates to compounds and methods that preferentially modulate cells expressing the tissue-protective erythropoietin receptor. The compounds of the invention are useful in preventing and treating diseases, such as anemia, organ injury, and diseases of the central nervous system, and as an adjunct to cellular treatments, such as stem cell therapies.


Patent
Stategics, Inc. | Date: 2010-08-10

The invention relates to compounds and their use in the treatment of thrombocytopenia resulting from diseases or conditions such as immune thrombocytopenic purpura, cancer chemotherapy, surgery, bone marrow or stem cell transplantation, radiation injury or treatment, chronic viral infection, and pancytopenia. The invention further relates to pharmaceutical compositions containing the compounds and compositions of the invention as well as methods for treating such diseases or conditions in a mammal, including a human, by administering to such mammal an effective amount of a selected thrombopoietin receptor agonist.


Disclosed herein are erythropoietin-mimetic compounds of Formula I, which modulate the survival, function, or differentiation of, for example, kidney cells, neurons, erythroid cells, or other erythropoietin-responsive cells. The present invention also relates to compounds and methods that preferentially modulate cells expressing the tissue-protective erythropoietin receptor. The compounds of the invention are useful in preventing and treating diseases, such as anemia, organ injury, and diseases of the central nervous system, and as an adjunct to cellular treatments, such as stem cell therapies.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 227.62K | Year: 2013

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) leads to a sudden impairment of renal function. The effects of AKI may be transient followed by full or partial recovery, but often progress to more severe renal insufficiency or end-stage renal disease. There are no approved therapies available. Previous studies support the view that, at sufficiently high doses, recombinant human (rh) erythropoietin (EPO) protects kidneys in animal models of AKI. However, high doses are needed to achieve renalprotection in preclinical studies, 5,000 IU/kg daily, because rhEPO does not efficiently access the extravascular system. The currently recommended doses of rhEPO in clinical settings are far lower (maximum to 900 IU/kg weekly), suggesting that dosing rhEPO at levels required to provide renal protection are not therapeutically viable. Consistent with this notion, the first clinical studies testing rhEPO in AK have provided mixed results, supporting the conclusion that more effective therapies are needed. RhEPO also associates with adverse effects due to its erythropoietic activity increasing the risk of thrombotic events. STATegics is focused on the discovery and development of small molecule cytokine mimetics and has identified non-erythropoietic EPO receptor (EPOR) agonists with potent tissue-protective activity. Using the human proximal tubule cell line HK-2, we find that these compounds activate EPOR and improve survival of the kidney cells in vitro. In addition, our studies indicate protective effects ofthe compounds on kidney function following chemically-induced AKI in vivo. Potent cytoprotective effects were also observed in rat and human neurons, illustrating broadly protective effects of these small molecules against cytotoxic challenges. In vitro safety assessment did not identify any safety concerns or off-target effects, and the compounds were well tolerated in an initial tolerability study in vivo. Importantly, no erythropoietic activity was observed at cytoprotective concentrations, in vitro orin vivo, suggesting a reduced risk of thrombotic events in vivo when compared to rhEPO. This Phase I program aims to establish a proof-of-concept for tissue- protective, non-erythropoietic small molecule erythropoietin EPOR agonists as potential disease-modifying agents in the treatment of AKI. The aim of the proposed studies is to evaluate and rank the protective effects of two promising compounds in this series using primary human and rat kidney cells in vitro and to test the ability of the most promisingcompound to protect rats from cisplatin-induced AKI in vivo. If the compound's kidney protective effects can be confirmed, our aim will be to expand into additional models of kidney injury, such as ischemia-reperfusion models. The latter studies would bethe subject of a future Phase II application, which would also include more thorough assessment of the compounds' safety in vitro and in vivo. Our long- term goal is to advance the lead compound into clinical testing for the treatment of AKI. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) leads to the sudden loss of renal function and presents a significant complication associated with 5-7% of hospital admissions and approximately 30% of patients admitted to intensivecare units. There are no approved therapies available. The proposed study focuses on the preclinical characterization of kidney-protective small molecules, operating through the tissue-protective EPO receptor, that have demonstrated encouraging cytoprotective properties.


PubMed | Stategics, Inc.
Type: Journal Article | Journal: Molecular pharmacology | Year: 2015

Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy. Here, we describe the discovery and characterization of the nonpeptidyl compound STS-E412 (2-[2-(4-chlorophenoxy)ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine), which selectively activates the tissue-protective EPO receptor, comprising an EPO receptor subunit (EPOR) and the common -chain (CD131). STS-E412 triggered EPO receptor phosphorylation in human neuronal cells. STS-E412 also increased phosphorylation of EPOR, CD131, and the EPO-associated signaling molecules JAK2 and AKT in HEK293 transfectants expressing EPOR and CD131. At low nanomolar concentrations, STS-E412 provided EPO-like cytoprotective effects in primary neuronal cells and renal proximal tubular epithelial cells. The receptor selectivity of STS-E412 was confirmed by a lack of phosphorylation of the EPOR/EPOR homodimer, lack of activity in off-target selectivity screening, and lack of functional effects in erythroleukemia cell line TF-1 and CD34(+) progenitor cells. Permeability through artificial membranes and Caco-2 cell monolayers in vitro and penetrance across the blood-brain barrier in vivo suggest potential for central nervous system availability of the compound. To our knowledge, STS-E412 is the first nonpeptidyl, selective activator of the tissue-protective EPOR/CD131 receptor. Further evaluation of the potential of STS-E412 in central nervous system diseases and organ protection is warranted.


Stategics, Inc. | Entity website

STATegics product pipeline is focused on allosteric small molecule modulators of clinically and commercially relevant cytokine receptors. STATegics small molecules, Allomimetics, offer unique competitive advantages when compared to recombinant proteins or antibodies particularly when bioavailability in tissues or the central nervous system (CNS) is required ...


Stategics, Inc. | Entity website

STATegics, Inc., all rights reserved


PubMed | Stategics, Inc.
Type: Journal Article | Journal: Current topics in medicinal chemistry | Year: 2015

Parkinsons disease (PD) is a neurodegenerative disease affecting more than a million people in the USA alone. While there are effective symptomatic treatments for PD, there is an urgent need for new therapies that slow or halt the progressive death of dopaminergic neurons. Significant progress has been made in understanding the pathophysiology of PD, which has substantially facilitated the discovery efforts to identify novel drugs. The tissue-protective erythropoietin (EPO) receptor, EPOR/CD131, has emerged as one promising target for disease-modifying therapies. Recombinant human EPO (rhEPO), several variants of EPO, EPO-mimetic peptides, cell-based therapies using cells incubated with or expressing EPO, gene therapy vectors encoding EPO, and small molecule EPO mimetic compounds all show potential as therapeutic candidates. Agonists of the EPOR/CD131 receptor demonstrate potent anti-apoptotic, antioxidant, and anti-inflammatory effects and protect neurons, including dopaminergic neurons, from diverse insults in vitro and in vivo. When delivered directly to the striatum, rhEPO protects dopaminergic neurons in animal models of PD. Early-stage clinical trials testing systemic rhEPO have provided encouraging results, while additional controlled studies are required to fully assess the potential of the treatment. Poor CNS availability of proteins and challenges related to invasive delivery limit delivery of EPO protein. Several variants of EPO and small molecule agonists of the EPO receptors are making progress in preclinical studies and may offer solutions to these challenges. While EPO was initially discovered as the primary modulator of erythropoiesis, the discovery and characterization of the tissue-protective EPOR/CD131 receptor offer an opportunity to selectively target the neuroprotective receptor as an approach to identify disease-modifying treatments for PD.

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