MALVERN, PA, United States
MALVERN, PA, United States
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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.68K | Year: 2016

DESCRIPTION provided by applicant Alzheimerandapos s disease AD affects an estimated million people worldwide this number is predicted to double in the next decade AD results from the degeneration and death of neurons in the hippocampus and the entorhinal cortex regions of the brain areas that are critical for learning and memory Patients in end stage AD lose the ability to perform basic bodily functions such as walking and swallowing and require round the clock care Ultimately fatal with no cure available AD is the sixth leading cause of death in the United States Current therapeutics which provide temporary symptomatic relief only in patients with early stage AD have serious side effects and cannot prevent neuronal death and disease progression Thus it is necessary to identify novel therapeutics that can actually halt the progression of AD Microscopic evidence has associated mitochondrial damage and the appearance of autophagic vacuoles with the onset of AD Moreover evidence suggests that mitophagy a regulatory form of autophagic degradation which is mediated by the kinase PINK and the ubiquitin E ligase Parkin and which normally eliminates dysfunctional mitochondria is overwhelmed and becomes inadequate to prevent accumulation of damaged mitochondria in AD affected neurons These results support the notion that activation of Parkin the key element of mitophagy is a promising therapeutic avenue that will act by enhancing compromised mitophagy in AD patients Overexpression of Parkin in the AD mouse model APPswe PSEN E ameliorates AD related symptoms and restores mitochondrial integrity Parkin exists in an auto inhibited andapos offandapos state in the cytosol via multiple intramolecular interactins genetic disruption of these interactions stimulates Parkin activity and promotes its translocation to dysfunctional mitochondria The goal of the present project is to mimic this effect with small molecules that activate Parkin by relieving Parkin auto inhibition thereby promoting mitophagy Such activators are expected to prevent the mitophagy deficiency induced neuronal death and consequently to hinder the progression of AD A TR FRET based homogeneous E assay will be utilized to conduct high throughput screening HTS of a diversity based and targeted small molecule library to identify potent and selective activators of Parkin Subsequently cellular proo of concept assays will be performed to measure the impact of the small molecule agonists on Parkin activation and mitophagy improvement In Phase II preclinical development will be pursued employing chemical optimization and efficacy ADME studies using relevant animal models The ultimate commercial goal is the development of a novel small molecule agonist that can be used to stop the progress of AD PUBLIC HEALTH RELEVANCE Alzheimerandapos s Disease AD is devastating in terms of mortality morbidity emotional strain and cost There is currently no cure approved treatments address symptoms but lose efficacy over time and do not prevent neuronal death the root cause of the disease In the proposed project activators of Parkin an enzyme from the ubiquitin pathway which helps to remove damaged mitochondria associated with neuronal cell death will be identified and in Phase II tested for their ability to stop the progression of symptoms of AD in an animal model


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 748.94K | Year: 2016

DESCRIPTION provided by applicant Numerous regulatory proteins are tightly controlled by ubiquitin conjugation and deconjugation and deviations from this dynamic process are manifested in clinical disorders such as cancer inflammation neurodegenerative disorders and metabolic diseases The deubiquitylase DUB USP plays multiple regulatory roles all of which are pro survival antiapoptotic One of its most intriguing roles is the furtherance of immune evasion whereby tumors employ various mechanisms to escape detection and killing by the host defense T and NK cell mediated immune system Abrogation of tumor tolerance induction has become a leading anticancer strategy as it should in principle work on a broad spectrum of cancers Clinical activity of antibodies to two receptors that trigger suppression of T cell defens CTLA and PD has led to USFDA approval of three biologicals for treating melanoma While the strategy is valid opportunities for improvement of the therapeutic index exist in the areas of mechanism multiple mechanisms can lead to tolerance suggesting that combination therapies will be needed for maximum efficacy and treatment cost a serious issue especially with biologicals The involvement of USP in sustaining immune evasion immediately suggests a therapeutic strategy inhibitors of USP destabilize the transcription factor Foxp which is needed to activate a population of Tcells Tregs that limit activation of tumoricidal T effector Teff cells Thus a USP inhibitor should break Treg induced tolerance allowing Teff cells to kill the tumor In Phase I Progenraandapos s selective USP inhibitor P was confirmed to diminish Foxp stability and eliminate Treg cellsandapos ability to induce tolerance by down regulating Teff cells as predicted Moreover P mediated anti tumor activity in the AE mesothelioma syngeneic tumor model only in immunocompetent mice thus suppressing tumor growth in this model by inhibiting T cell anergy and not by direct cytotoxic effects of the kind observed in other models Also in Phase I the potency and drug like properties of P were improved by the generation of a series of compounds with EC nM while maintaining selectivity and efficacy in cellular and in vivo proof of concept models In Phase II lead optimization will focus on further improvement of pharmacological properties PK toxicology and efficacy studies will guide chemical synthesis The goal is to identify potent and selective compounds with efficacy against lung cancer and other tumor models with the ultimate commercial goal of initiating clinical development PUBLIC HEALTH RELEVANCE Immuno oncology based treatment of cancer promises to increase effectiveness of cancer therapy by harnessing the patientandapos s own immune system to remove the invading tumor rather than by directly killing tumor cells and other cells of the body leading to harmful side effects Several classes of drug may be needed to achieve the maximum activation of the immune defense and the proposed project continues the development of a class of molecule that has enabled T cells to eradicate tumors in animal models either singly or in combination with other immuno oncology agents The project will identify a clinical candidate s


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.80K | Year: 2015

DESCRIPTION provided by applicant Progressive loss of cognitive skills a hallmark of neurodegenerative diseases such as Alzheimerandapos s AD represents a major challenge to healthcare implementation No satisfactory treatments for AD currently exist and multiple approaches will be necessary for successful therapeutic management Among these approaches is effective pharmacologic intervention to ameliorate cognitive deficits associated with AD and other neurodegenerative diseases Ubiquitin E ligases are a class of molecular target recently linked to a variety of pathologies including synaptic function and regulation of te response to oxidative stress in neurons and other cell types IDOL is one such ligase it is known to ubiquitylate and promote the degradation of certain receptors including ApoER and VLDLR which are the major receptors for the glycoprotein Reelin in the brain Reelin is a principal regulator of memory cognition via signal transduction mediated by ApoER and VLDLR Reelin binding increases long term potentiation and synaptic plasticity Numerous knock out and knock in studies as well as murine models show that Reelin exerts a positive effect on learning and memory thus augmentation of Reelin signaling is very likely to offer benefit in treating cognitive decline in AD and related diseases Because IDOL is responsible for down regulating Reelin the therapeutic hypothesis addressed in the proposed project is that IDOL is a tractable novel target for developing small molecule inhibitors that will augment Reelin signaling Inhibitors of IDOL are expected to increase ApoER and VLDLR levels in the brain and enhance Reelin mediated synaptic plasticity Using a thermal shift based pilot screen Progenra has discovered several IDOL inhibitors and preliminary data demonstrate that one of these IDOL inhibitors P stabilizes ApoER In the proposed project novel small molecules that enhance or stimulate Reelin signaling in the brain by interfering with IDOL and stabilizing ApoER and VLDLR will be discovered and advanced toward pre clinical development Inhibitors already in hand will be developed by chemical optimization and additional inhibitors will be identified by further screening of Progenraandapos s entire small molecule library and optimized similarly Selected inhibitors will be evaluated using a combination of biochemical cellular and in vivo model systems for their ability to stabilize ApoER and VLDLR as well as to modulate Reelin signaling biomarkers In Phase II the most promising compounds will advance into preclinical development using appropriate animal models for memory and cognition PUBLIC HEALTH RELEVANCE The proposed project addresses the progressive loss of cognitive skills observed in neurodegenerative diseases such as Alzheimerandapos s Disease AD Preventing or reversing this decline will be an important component of future treatment strategies for AD Progenra has discovered inhibitors of a ubiquitin pathway enzyme IDOL that are able to stabilize two neuronal receptor molecules ApoER and VLDLR that are important in promoting cognition and memory It is proposed to develop these molecules and others like them for treatment of AD and related neurodegenerative diseases


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 205.20K | Year: 2015

DESCRIPTION provided by applicant Millions currently suffer from Alzheimerandapos s disease AD as life expectancy increases it will become increasingly widespread AD results from the degeneration and death of neurons of the hippocampus and entorhinal cortex End stage patients require continuous care and AD is currently the sixth leading cause of death in the U S There is currently no cure approved treatments aimed at improving cognition and slowing progression focus primarily on increasing the level of acetylcholine in the brain Such treatments which have serious side effects and relieve AD symptoms only for a limited time cannot prevent neuronal death Thus an urgent need exists to identify novel agents that prevent AD progression by acting on targets that mediate neuronal death The mitochondrion is such a target excess dysfunctional mitochondria in AD linked neurons lower energy efficiency and release reactive oxygen species contributing to neuronal death The dysfunctional mitochondria are cleared by phosphorylation and ubiquitin mediated autophagy mitophagy or degradation in auto phagosomes The ubiquitin pathway component consists of the conjugating enzyme parkin which tags defective mitochondria with ubiquitin for removal and the deubiquitinating enzyme USP which deconjugates ubiquitin preventing the removal of defective mitochondria Normally in AD patients the ability to clear defective mitochondria is overwhelmed and replacement of parkin function by overexpression can rescue AD symptoms in vivo Moreover USP knockout has been shown to enhance parkin activity and increase mitochondrial integrity in neurons These findings lead to the hypothesis that USP is a novel target for developing small molecule inhibitors for treatment of AD USP inhibitors are expected to prevent mitophagy deficiency induced neuronal death thereby hindering progression of AD It is proposed to identify novel modulators of USP by screening a diverse collection of small molecules An enzymatic based USP assay for high throughput screening HTS will be configured and Progenraandapos s compound collection will be screened Confirmed hits will be reordered along with a subset of related analogs and profiled against a series of DUBs and other proteases before initiating a hit to lead optimization program The most promising compounds from this program will be examined in cellular models of mitophagy rescue In phase II the most interesting compounds will be progressed to hit to lead medicinal chemistry optimization with associated DMPK and additional cellular and animal model studies The commercial goal is a novel drug to treat AD PUBLIC HEALTH RELEVANCE Alzheimerandapos s disease AD is devastating in terms of mortality morbidity emotional strain and cost There is currently no cure approved treatments address symptoms but lose efficacy over time and do not prevent neuronal death the root cause of the disease In the proposed project inhibitors of a newly discovered enzyme from the ubiquitin pathway which helps to maintain neuronal cell death will be identified and tested for their ability to stop the progression of symptoms of AD in an animal model Appropriate inhibitors will be developed as novel treatments for AD


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 222.94K | Year: 2015

DESCRIPTION provided by applicant Obesity is a global issue Life threatening medical disorders associated with obesity include cardiovascular disease type diabetes and likely certain types of cancer these would be minimized if obesity could be better controlled In addition healthcare costs would be increasingly manageable in proportion to the reduction in obesity To supplement diet and exercise based measures to control obesity various drugs have been developed Most currently approved drugs such as lorcaserin Belviq and phentermine topiramate Qsymia rely on appetite suppression and subsequent reduced food intake while another orlistat marketed as Xenical and Alli works by reducing fat absorption In addition to being limited to populations of susceptible patients weight loss drugs are compromised by side effects often cardiovascular or psychiatric Thus additional novel therapeutics are being sought to combat obesity focusing on molecular mechanisms for example ubiquitylation deubiquitylation that can be affected pharmacologically to halt or reverse accumulation of excess fat Ubiquitin conjugating enzymes known as E ligases are a very large family of enzymes many of which have been linked genetically and or biochemically to various pathologies One ligase HRD is associated with adipose tissue knockout or knockdown of this ligase in mice leads to a large reduction in white adipose and weight loss Its ubiquitylation target appears to be PCG a transcriptional co activator involve in fatty acid metabolism and mitochondrial biogenesis It is therefore proposed here to develop small molecule inhibitors of HRD for treatment of obesity To accomplish this assays that have been used successfully at Progenra to discover molecules that are active against other physiologically relevant E ligases will be adapted to screen for novel HRD inhibitors for characterization and development as therapeutic agents for obesity Selected hits from the screen of Progenraandapos s small molecule collection will be evaluated for predicted physiological activity in cellular models based on PCG associated cell markers developed by Progenraandapos s collaborator Professor Toshihiro Nakajima of Tokyo Medical University In Phase II selected molecules with acceptable chemical properties and cell based activity will be put into pre clinical development for anti obesity therapy PUBLIC HEALTH RELEVANCE To improve the general health and quality of life of individuals and to contain healthcare costs it is desirable to find an effective treatment for obesity Curren anti obesity drugs are not ideal as they are of limited applicability and can produce dangerous side effects A novel target enzyme from the ubiquitin pathway HRD has been linked genetically to fat accumulation and weight gain so inhibitors of this enzyme will be identified and developed to treat obesity


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 339.09K | Year: 2016

DESCRIPTION provided by applicant The approval of the cystic fibrosis CF drug invocator for patients with the G D mutation validates CFTR modulators for improving clinical outcomes in CF For most CF patients with F del and other mutations however multi drug combination therapy will likely be necessary and sensitive biomarkers of augmented CFTR function in response to various agents will be needed In vivo assays employed to date have not been predictive of efficacy neither do they correlate well with individual patient improvement The proposed project combines two recent advances by researchers at the University of Alabama at Birmingham UAB and the Massachusetts General Hospital MGH to produce a novel in vitro human cell biomarker that will predict CFTR function in individual patients methods which allow primary human epithelial cell cultures of nasal origin HNE to proliferate rapidly and to maintain an airway phenotype and a pioneer imaging technology Micro Optical Coherence Tomography OCT which permits simultaneous and co localized quantification of multiple elements of airway function including mucociliary transport demonstrating reproducible anatomic differences between CF and normal human explants and functionally characterizing in situ fully differentiated primary human bronchial epithelial cells HBE grown in culture OCT can also directly visualize dynamic differences between CF and wild type tissues simultaneously measuring collapsed airway surface liquid ASL height reduced cilia beat frequency CBF delayed mucus transport MCT and increased mucus viscosity Preclinical data indicate primary human airway cell cultures strongly predict ion transport efficacy of CFTR potentiators and correctors on a group wise basis Progenra will work with UAB and MGH to develop and commercialize the novel HNE culture as an in vitro biomarker for CFTR function employing OCT for simultaneous detection of the markers In Phase the validity and utility of combining primary nasal cells with optimized and automated OCT based analysis of the functional microanatomy will be established as a tool to predict efficacy in individual patients It will first be demonstrated that an automated OCT imaging acquisition and analysis system can distinguish the functional microanatomy i e ASL PCL depth CBF MCT and viscosity of normal and CF differentiated HNE It will then be ascertained whether HNE cells from twenty five G D CF subjects enrolled in the GOAL study an open label observational trial of invocator predict therapeutic response to invocator on an individual basis In Phase II the study will be expanded to patients and five different mutant CFTR genotypes The ultimate commercial goal is to develop an experimental system that faithfully predicts the responses to various CFTR therapies on an individual basis PUBLIC HEALTH RELEVANCE Invocator is the first drug approved to treat the cause of cystic fibrosis rather than simply manage its symptoms This drug works in only a small percentage of patients however the majority will likely require combinations of drugs to achieve success A new human cell culture system is being sought to predict how a given patient with a charactistic genetic signature will respond to various drugs and the proposed project aims to develop such a system utilizing novel methods of cell growth and optical imaging so that each cystic fibrosis patientandapos s cells can be easily analyzed and a treatment protocol developed


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 205.89K | Year: 2016

Asthma is a major public health problem affecting million people worldwide While no cure is available symptoms can be managed with corticosteroids and agonists which can exert deleterious side effects Improved targeted therapies are needed for steroid resistant and other forms of asthma A complex disease asthma entails chronic inflammation hyper reactivity and remodeling of the airways and immunity driven by TH and TH cells contributes to the pathogenesis of asthma subtypes Cytokines secreted by these immune cells act to recruit eosinophils and neutrophils leading to the pathology of asthma further crosstalk between TH and TH responses ultimately leads to further amplification and elevation of inflammation Targeted suppression of TH and TH differentiation and or responses is the general approach taken here for treating the underlying drivers of asthma In particular the ubiquitin pathway regulates immune responses and ubiquitin based drugs may have utility in controlling asthma For example the E ligase Itch suppresses both TH and TH differentiation and cytokine production upon activation by Nedd family interacting protein Ndfip Progenra has identified small molecule Ndfip mimetics which are able to activate Itch impairing IL production and promoting Treg rather than TH cell differentiation Recently USP a deubiquitylase has been shown to be critical for TH differentiation by stabilizing TH specific transcription factor RORgammaT and pharmacological inhibition of USP blocks TH differentiation Thus one can selectively target TH and TH differentiation by modulating USP function It is therefore proposed here to discover and develop selective small molecule inhibitors of USP these are expected to limit TH differentiation dampening inflammatory asthmatic responses In addition USP inhibitors will be combined with Progenraandapos s small molecule Ndfip mimetics Itch activators to selectively impair TH and TH differentiation To accomplish this therapeutic goal high throughput screening for USP inhibitors will be conducted employing Progenraandapos s screening platform and member small molecule library Cellular proof of concept assays will be conducted on selected hits to evaluate their effect on TH differentiation and cytokine production in relevant in vitro models In Phase II lead optimization and additional preclinical studies will be performed with selected inhibitors to ascertain their ability to modulate USP functions and to dampen inflammation in relevant mouse models The ultimate commercial goal is the development of novel small molecule agents that can be used in combination to treat steroid resistant asthma Asthma is a complex disease driven by T cells of the immune system that activate inflammatory cytokine secretion causing asthma symptoms Progenra has discovered small molecule ubiquitin pathway modulators that can reduce cytokine production by interfering with the T cells A second ubiquitin pathway enzyme USP has been found to activate T cell dependent cytokine production In this project inhibitors of USP will be developed to use alone or in combination with the original T cell modulators to eradicate the symptoms of asthma produced by inflammatory cytokines the combination treatment is expected to be very powerful


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 205.00K | Year: 2016

Approximately individuals worldwide suffer from cystic fibrosis CF a debilitating ion transport disease characterized by abnormal mucus secretion primarily involving the lungs Following years of symptom management as the only treatment option Kalydeco ivacaftor or VX and Orkambi a combination of ivacaftor plus lumacaftor VX were approved by the FDA to treat the underlying cause of CF Because ivacaftor alone is approved for only of CF patients and ivacaftor lumacaftor while approved for nearly half of CF patients improves lung function to a lesser degree than ivacaftor does in the other subset of patients new drugs addressing the root cause of CF in a majority of patients are needed CF patients harbor mutations in the cystic fibrosis transmembrane conductance regulator CFTR protein which localizes to the cell membrane and controls salt transport and thus water flow Such mutations decrease the amount and or function of CFTR leading to CF pathologies The most widespread of several CF mutations worldwide is the deletion F which causes improper folding of CFTR As a result CFTR is degraded before it can reach the membrane where it must be functional Small molecules called correctors e g VX work by promoting trafficking of mutant CFTR to the cell surface Because existing CF treatments are limited efforts are warranted to target other mechanisms of increasing the levels trafficking and or functionality of CFTR F to develop novel drugs for single or conjoint use to treat CF The ERAD pathway of the ubiquitin signaling system has been exploited to yield inhibitors of gp a major ERAD ligase that degrades misfolded CFTR such inhibitors are predicted to increase membrane levels of mutant but still active CFTR providing therapeutic benefit In the course of this work a new mechanism for CFTR preservation not due to direct inhibition of gp was uncovered A class of false positives in the gp inhibitor screen are able to stabilize CFTR apparently by inhibiting ubiquitin binding UBA domains leading to blocked CFTR degradation and increased levels of CFTR which could increase the amount of CFTR at the cell surface especially in combination with correctors such as VX Initial proof of concept for this model has been obtained Accordingly in the proposed studies a FRET based assay for UBA domain inhibitors will be employed to screen for compounds that target UBA domains and positives will be tested for potency and selectivity Inhibitors from this screen are expected to increase levels of functional CFTR improving the regulation of mucus in the lungs of CF patients selected compounds will therefore be evaluated for proof of concept in biochemical and cell based models of cystic fibrosis Cystic fibrosis CF is a debilitating disease for which symptom management remains the only treatment option for a majority of patients Although recently approved drugs Kalydeco and Orkambi can treat the underlying cause of CF quantitative and qualitative defects in the CFTR protein which regulates ion transport in the lung in some patients additional more effective therapies are needed Here it is proposed to develop such a drug from compounds discovered to interfere with ubiquitin binding domains resulting in improved content and activity of CFTR This drug will be tested singly or in combination with the approved drugs


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.97K | Year: 2014

DESCRIPTION (provided by applicant): Many regulatory proteins are themselves tightly controlled by ubiquitin conjugating and deconjugating enzymes, whose dysfunctional forms are implicated in numerous diseases, including cancers. USP7, a deubiquitylating enzyme, regulates ubiquitylation and, thereby, stability of the E3 ligase HDM2, which in cells effects ubiquitylation and promotes proteasomal degradation of the tumor suppressor p53 as well as a number of other proteins such as FOXO4, PTEN and claspin. Thus, inhibiting USP7 can impact both p53 wild type and mutant tumors. In addition, by de-ubiquitylating and preserving the transcription factor Foxp3, USP7 increases T regulatory cell (Treg) mediated suppression of tumor-infiltrating T effector cells, the latter being associated with improved clinical outcome for many solid tumors, including lung cancers. Thus, USP7 functions to limit immune cell-mediated antitumor defenses. The observation that the accumulation of Foxp3+ Treg cells at the tumor or in d


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.77K | Year: 2014

DESCRIPTION (provided by applicant): The degradation of most cellular proteins is regulated by coordinated addition and removal of ubiquitin by families of ubiquitin E3 ligases and deubiquitylating enzymes (DUBs) respectively. DUBs proteolytically cleave ubiquitin molecules from proteins resulting in modifications of protein activity, localization and function. Several DUBs are aberrantly regulated in cancer, including the best studied, USP7, selective inhibitors of which are active in cancer models. A second DUB, USP22, is another validated anticancer target, being one of 11 genes in the death-from-cancer gene signature, a component of the human SAGA transcriptional cofactor complex regulating myc transcription, and a regulator of the expression of p21, thehistone deacetylase Sirt 1, and p53 activity. USP22 is overexpressed in oral squamous cell carcinoma, breast, non-small cell lung, colorectal, and other cancers and its expression is inversely correlated with survival. Unlike most other DUBs, USP22 e

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