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HUMMELSTOWN, PA, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 316.92K | Year: 2012

DESCRIPTION (provided by applicant): The goal of this program is to develop novel inhibitors of human neutral ceramidase (ASAH2) that are effective as therapeutic agents for Inflammatory Bowel Diseases (IBDs). Sphingolipids are being increasingly recognized as key mediators of inflammation, and are known to mediate the effects of pro-inflammatory cytokines such as tumor necrosis factor-? (TNF?) that are of central importance in IBD. Accumulating evidence demonstrates that sphingosine-1-phosphate (S1P) produced by the combined action of sphingomyelinases, neutral ceramidase and sphingosine kinases within gastrointestinal epithelial and endothelial cells drives the inflammation processes in IBD. Therefore, sphingolipid metabolizing enzymes are potential molecular targets for the development of new drugs for the treatment of IBDs. Because of the pivotal role of ceramidases in regulating inflammation, Apogee Biotechnology Corporation is developing ceramidase inhibitors to treat inflammatory diseases. We have identified the first non-lipid, i.e. drug-like , inhibitors of human ASAH2, which is the dominant ceramidase isozyme expressed in the human gastrointestinal tract. In this Phase 1 SBIR project, we will evaluate the pharmacology and anti-IBD activity of three novel ceramidase inhibitors (representing three chemotypes of ceramidase inhibitors currently being optimized) in two in vivo models of IBD through the following Specific Aims: 1. To synthesize and evaluate the toxicity and pharmacokinetics of novel ceramidase inhibitors. We have identified three chemotypes of drug-like ceramidase inhibitors by high-throughput screening and medicinal chemistry. The lead compound within each of these chemotypes will be synthesized in gram quantities for in vivo testing.The Maximum Tolerated Dose and pharmacokinetics of each of these ceramidse inhibitors will be determined to optimize treatment protocols in the IBD models. 2. To evaluate the therapeutic efficacies of ceramidase inhibitors in the DSS model of ulcerative colitis. Each of the novel ceramidase inhibitors will be tested for efficacy in the dextran sulfate sodium (DSS) model of ulcerative colitis in mice, using a combination of clinical, morphological and biochemical endpoints. 3. To evaluate the therapeutic efficacies of ceramidase inhibitors in the TNBS model of Crohn's Disease. The efficacies of the three novel ceramidase inhibitors will be examined in the TNBS model of Crohn's disease in mice, utilizing similar evaluation endpoints as in Aim 2. This work will provide the first proof-of-principle efficacy studies of ceramidase inhibitors in widely- utilized models of IBD. We have extensive experience with the proposed IBD models and a proven track record for bringing sphingolipid-targeted drugs into clinicaltrials. We believe that the use of neutral ceramidase inhibitors for te treatment of IBD is an innovative approach that is likely to be rapidly translated to the clinic. PUBLIC HEALTH RELEVANCE: According to the Centers for Disease Control and Prevention, the estimated incidence of IBD in the US is 1.4 million persons, with an overall health care cost of more than 1.7 billion. This chronic condition is without a medical cure and commonly requires a lifetime of care. Over the long term, up to 75%of patients with Crohn's disease and 25% of those with ulcerative colitis will require surgery, making it clear that new therapeutic approaches are needed. Extensive work, including our Preliminary Studies, suggests that inhibition of neutral ceramidase may provide a new therapy for these diseases. The proposed studies will provide the first test of this hypothesis.

Musc Foundation For Research Development and Apogee Biotechnology Corporation | Date: 2010-05-10

Ischemia-reperfusion injury remains a primary cause of morbidity and mortality in individuals who experience disruption of normal blood flow to one or more major organs. For example, there are no clinically proven strategies that prevent acute renal failure following cardiac surgery. The present invention provides a variety of methods for the treatment or prevention of ischemia-reperfusion injury. In one aspect of the invention, a method for treating or preventing ischemia-reperfusion injury includes administering to a subject an effective amount of a sphingosine kinase inhibitor. Sphingosine kinase inhibitors are very effective in the protection against IR-induced acute renal failure and liver failure. Moreover, the effects occur very early after administration, requiring only a very short time of treatment. Toxicology studies with sphingosine kinase inhibitors demonstrate that they have low toxicity, even in long-term treatment.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 593.45K | Year: 2013

DESCRIPTION (provided by applicant): Radiation-induced production of pro-inflammatory and pro-fibrotic cytokines results in chronic and irreversible damage to the lungs. To date, no agent has demonstrated a sufficient safety profile to be utilized as a clinical drug for mitigating damage from exposure to radiation from accidental or terroristic nuclear events. Consequently, there is a great need for new, mechanistically-targeted drugs that can be utilized to mitigate radiation poisoning of humans following unintended exposure. Many studies have implicated sphingolipid metabolism as a critical mediator of inflammatory and fibrotic processes. Inflammatory and pro-fibrotic cytokines produced by radiation exposure (e.g. TNF and TGF ) activate sphingomyelinases and ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1P). It is established that SK activation and production of S1P are essential for signaling responses to inflammatory cytokines, including their ability to induce adhesion molecule expression via activation of NF?B. Similarly, collagen synthesis in response to TGF is dependent on S1P production by SKs. Therefore, SKs are rational new targets for drugs that attenuate damaging inflammation and fibrosis. Apogee Biotechnology Corporation has identified the first orally-available SK inhibitors with activity in vitro and in vivo. The lead SK2 inhibitor, designated as ABC294640, has antitumor and anti-inflammatory activitiesin several in vivo models, while exhibiting very low toxicity to the animal. Our Preliminary Studies indicate that treatment of mice with ABC294640 protects against toxicity from total body or abdominal irradiation when the compound is given either pre-exposure or post-exposure. We hypothesize that suppression of SK2 activity by ABC294640 will mitigate pulmonary fibrotic damage from exposure to ionizing radiation. To establish justification for moving ABC294640 toward clinical trials for radiomitigation,we will conduct the following Specific Aims: 1) To determine the mechanism for ABC294640 protection against cytokine-induced fibrotic responses in cultured human fibroblasts; and 2) To characterize the ability of ABC294640 to protect against pulmonary fibrosis from thoracic irradiation. These studies will provide the experimental validation needed to justify future confirmatory studies in non- human primates, and ultimately clinical trials in humans. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Exposure to ionizing radiation, which can occur through accidental or terroristic nuclear events, causes damage to a variety of organs including the lungs because of chronic inflammation and fibrosis. We have developed an orally-available inhibitor ofthe enzyme sphingosine kinase-2 that has anti-inflammatory activity in several animal models. We will examine the effects of this compound in mice to determine its ability to reduce radiation-induced lung damage.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 260.99K | Year: 2009

DESCRIPTION (provided by applicant): Derivatives of camptothecin (CPT) that inhibit Topoisomerase I (Top1) activity have demonstrated clinical utility in the treatment of various cancers. However, limitations in CPT pharmaceutical properties have driven the search for new CPT-like poisons that target the Top1 protein-DNA cleavage complex. We hypothesized that bifunctional agents that simultaneously bind to the DNA minor groove and the nose-cone region of the Top1 protein would be effective poisons with pharmaceutical properties that are superior to the CPT congeners. Such compounds also should be effective against tumors that are otherwise resistant to the CPT structural class of poisons and should generally exhibit reduced toxicity compared to the CPT- class of agents such as topotecan. Structural insights from Top1-DNA crystal structures were used to design a small library of N-acetyl dipeptides linked to Hoechst 33258, a DNA minor groove binder. Screening of the library against a in vitro assays and subsequent library deconvolution afforded a high affinity (EC50 ~ 50 nM) agent, LL217, that also caused growth arrest of several tumor cell lines. Subsequent replacement of the Hoechst with a phenyl- substituted monobenzimidazole provided the agent MB1 that exhibits tumor cell line killing activity similar to LL217 but with substantially reduced off-target effects. Biochemical assays performed with LL217 and MB1 demonstrate that the primary modality of action in tumor cell lines is cell cycle arrest due to inhibition of Top1 activity. Our long-term goal is to translate MB1 into a clinically efficacious drug. Our immediate goal is to produce a refined lead compound with sufficient tissue culture and murine xenograft data to support further development. The immediate goals will be achieved via four specific aims: (1) the structure of MB1 will be slightly modified to facilitate solution phase syntheses, (2) the in vitro and cellular activities of the MB1 derivatives will be assayed and compared to topotecan, (3) the potential therapeutic efficacy of MB1 will be evaluated in murine xenograft tumor models as compared to topotecan, and (4) the pharmaceutical properties of MB1 and topotecan will be evaluated. PUBLIC HEALTH RELEVANCE: Cancer has recently surpassed cardiovascular disease as a major cause of morbidity and mortality in the United States. Although new classes of chemotherapeutic agents are needed, it is also desirable to develop agents with improved pharmaceutical properties that target clinically validated targets. The camptothecin class of agents used in the clinic specifically target the Topoisomerase 1 enzyme. However, their poor solubilities and stabilities require the use of large doses, which increases the chances for adverse effects to the patient. The agents described here also target Topoisomerase 1, but they are expected to be more bioavailable and, thus, offer an improvement to the camptothecin class of agents. Because these agents are also structurally distinct, it is expected that they will be clinically efficacious against cancers that have developed resistance to the camptothecins.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 526.91K | Year: 2009

DESCRIPTION (provided by applicant): Severe shortages of donor organs limit the use of orthotopic liver transplantation (LT), the only proven therapy for end-stage liver diseases. Primary non-function (PNF) of liver grafts after transplantation typically results in recipient death or necessitates retransplantation, which further exacerbates the shortage of donor livers. Unfortunately, effective therapies for PNF are not yet known. Liver ischemia/reperfusion (IR) injury plays an essential role in initial poor graft function and PNF. Our recent exciting observations indicate that inhibition of sphingosine kinase (SK) dramatically decreases PNF after hepatic warm IR in vivo, suggesting that sphingolipids may be key regulators of IR injury. In particular, SK is a critical regulator of inflammatory cells that are of central importance in IR injury. Our data also show that the SK inhibitor blocks mitochondrial dysfunction induced by IR, a major mechanism of cell death. Therefore, we hypothesize that SK is a key molecular target for the development of new drugs to prevent and/or treat PNF after LT. We have recently identified novel inhibitors of SK that more potent than any other known SK inhibitor, while being of high specificity and low toxicity. We hypothesize that these SK inhibitors can be used to attenuate IR-induced liver injury and thereby improve the outcome of LT. Therefore, we will conduct the following studies during Phase I of this STTR project: Specific Aim 1. To synthesize sufficient amounts of SK inhibitor ABC294640 for in vivo studies, characterize its solubility and stability in cold storage solution and determine its penetration into liver in vivo and explants during cold storage. Specific Aim 2. To determine the effects of ABC294640 in lean liver transplantation and investigate the mechanisms of protection. Specific Aim 3. To determine the effects of ABC294640 in fatty liver transplantation. Taken together, inhibitors of SK represent a novel approach toward the identification of new anti-IR injury drugs. We will use a rat orthotopic LT model in combination with state-of-the-art intravital multiphoton microscopy and molecular biology techniques to evaluate the clinical potential of a lead SK inhibitor as a new therapy that can be taken to the clinic to improve the outcome of LT. PUBLIC HEALTH RELEVANCE: Use of live-saving liver transplantation techniques is limited by a severe shortage of usable donor livers, resulting in the deaths of patients on recipient waiting lists. Ischemia-reperfusion injury plays an essential role in the initial poor function and consequent failure of many liver grafts. Accumulating information suggests a role for sphingosine kinase (SK) activity in hepatotoxicity following ischemia, and our Preliminary Studies indicate that this can be dramatically improved by an SK inhibitor. The proposed studies will determine if this compound has potential for further development as a hepatoprotective drug for liver transplantation.

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