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SAN DIEGO, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 214.65K | Year: 2015

DESCRIPTION provided by applicant Developing new ways to treat prostate cancer is a significant challenge Prostate cancer is the second leading cause of cancer related deaths for men in the United States In this resulted in an estimated deaths Prostate cancer therapeutic options are limited to surgery and or combinations of chemotherapy and radiation Unfortunately late stage diagnosis of prostate cancer renders current therapies ineffective The effectiveness of relatively new targeted treatments remains to be shown There is an urgent major unmet medical need for the development of selective treatments for prostate cancer Our new approach to prostate cancer is completely different and focuses on inhibition of a key molecular pathway by a non toxic compound We have discovered and optimized a small molecule i e that selectively and potently inhibits a key molecular pathway The overall Goal is to test this novel small molecule as an inhibitor to suppress prostate cancer progression by targeting a key signaling pathway and enhance currently used chemotherapeutics Compound is non toxic pharmaceutically suitable for in vivo applications and possesses a novel mechanism of action Based on extensive in vitro and in vivo preliminary data we have strong support that will inhibit prostate cancer proliferation in vivo and enhance currently used chemotherapeutics The novelty of this project comes from the unique druggable target of the proposed anti prostate cancer compound The hypothesis that inhibition of a single molecular pathway can result in blocking three mechanisms of prostate cancer including proliferation migration and apoptosis and also enhance currently used chemotherapeutics is novel The proposed work can be readily accomplished because of the expertise of the team The work will be divided into two straightforward Specific Aims The Aims of the work include a Show that lead compound has chemical and metabolic stability b Do IND enabling safety and PK studies of in preparation for orthotopic xenograft studies and Do efficacy studies of in the presence and absence of enzalutamide in subcutaneous and human patient derived intrafemoral bone niche xenograft models to show enhanced inhibition of tumor growth and pathology of xenografts in mice The results obtained will afford fundamental information about a new approach to treat prostate cancer The development of non toxic inhibitors of molecular pathways crucial to prostate cancer represents a novel approach and addresses a major unmet medical need because the clinical utility of available approaches for treating bone niche human prostate cancer is limited We hypothesize that lead compound will enhance enzalutamide inhibition of prostate cancer proliferation in an in vivo orthotopic xenograft animal model of prostate cancer with minimal side effects and thus provide feasibility of a novel therapeutic strategy to treat prostate cancer PUBLIC HEALTH RELEVANCE Prostate cancer is a leading cause of cancer related deaths in the United States A promising non toxic lead compound has been identified and characterized in vitro and in vivo as a potent anti prostate cancer compound Successful completion of this work will lead to developing that decreases prostate cancer proliferation as evidenced by in vivo xenograft animal model studies The compounds will work with minimal side effects thus providing evidence for novel therapeutic utility


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 172.54K | Year: 2011

DESCRIPTION (provided by applicant): Over 1-2% of Americans greater than 65 years of age have heart disease. According to the American Heart Association, heart failure is one of the most common causes of hospitalization for patients over 65 years of age inthe Western world and as the population ages, this situation will only get worse. Currently, more than 5 million Americans suffer from heart failure. In 2009, the economic cost (direct and indirect) to US society for heart disease was in excess of 37 billion per year. Certain diseases related to heart muscle failure or heart muscle weakening are treatable with drugs or devices such as defibrillators, pacemakers or implanted pumps. However, in heart attacks, when heart muscle cells die, transplantation becomes the only option because cardiomyocyte regeneration in the human heart is generally very limited. Today, unfortunately, there is considerably less heart transplantation tissue available than the current need for transplants. Tens of thousands of heartscould be used each year for transplants but only about 2,000 hearts are available. Chemical biology approaches to embryonic stem cell (ESC) research offers considerable promise for rectifying this problem. However, despite progress, increasing the efficiency of stem or progenitor cells to become human cardiomyocytes has been very challenging. The main problem with increasing the yield of cardiomyocytes is the lack of effective ways to induce ESCs to afford cardiomyocytes involved in cardiogenesis. A critical issue is the low yields of cardiomyocytes from in vitro differentiation processes. An economically viable biotechnological process using readily available and inexpensive differentiation agents is needed. Herein, we propose to use a powerful combinationof high content and high throughput cellular assays and dynamic medicinal chemistry to develop pure, easy to make, small molecule toolbox compounds to promote the induction of hESCs that will differentiate into cardiomyocytes. A promising new cardiomyocyte differentiation agent (i.e., compound 1) has been identified and refinement and development of this agent is the focus of this proposal. The Specific Aims include: 1) Test compounds structurally related to 1 as inducers of cardiomyocytes in a validatedmouse ESC assay and 2) Test potent compounds identified in Aim 1 in a validated human ESC assay for cardiomyocyte differentiation. Based on our encouraging Preliminary Results successful completion of the proposed work will provide an inexpensive toolboxof reagents useful for the induction of cardiomyocytes from human ESCs of utility in a biotechnological sense. Preparation of human cardiomyocytes in this manner will provide large numbers of cardiomyocytes and will be of widespread use to the CRO, biotechnology or Big Pharma industry to help individuals that suffer from heart failure including myocardial infarct as well as to do drug safety tests with human cardiomyocytes to decrease adverse drug-drug interactions and develop safer drugs. PUBLIC HEALTH RELEVANCE: For heart attack victims, stem cell therapy may provide a way to regenerate damaged heart muscle cells. Current therapies are only able to improve heart function. The goal of our work is to use chemical biology to develop small molecule toolbox compounds that will stimulate stem cell differentiation and produce cardiomyocytes. Ultimately, the results from this work will provide reagents for use to grow cardiomyocytes for use in a biotechnology process to treat heart disease.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 172.06K | Year: 2011

DESCRIPTION (provided by applicant): It is estimated that more than 5 million Americans suffer from heart failure. The economic cost to US society for heart disease was almost 40 billion per in the year 2009. Currently, people with late-stage heart failure have only two treatment options, a heart transplant or implantation of a mechanically-assisted heart device but in the US, just over 2,000 hearts/year are available for transplantation. Heart diseases related to heart muscle failure or heart muscle weakening are treatable with drugs or devices such as defibrillators, pacemakers or implanted pumps. However, in heart attacks, when heart muscle cells die, transplantation becomes the only option because cardiomyocyte regeneration in the human heart is generally very limited. Current approaches used or in clinical trials are not designed to regenerate heart muscle but rely on improving remaining heart function. In the case of stem cell (SC) therapies in clinical trials, beneficial effects are due to paracrine signals from transplanted cells or persistence as vascular endothelial cells. Because of the large heart disease patient population, an intense effort to develop myocardial cell replacement therapies is underway. Production of cardiomyocytes in a biotech sense is a very important goal that would have considerable applications in both drug discovery and heart failure treatment. However, despite progress, increasing the efficiency of stem or progenitor cells to become human cardiomyocytes has been very challenging. The main problem with increasing the yield of cardiomyocytes is the lack of effective ways to induce ESCs to afford cardiomyocytes involved in cardiogenesis. A critical issue is the low yields of cardiomyocytes from in vitro differentiation processes. The need is to produce human cells that mimic the cardiac cell's response and physiological behavior in an efficient and cost-effective manner is paramount. The ability to differentiate SCs into cardiac cells on a large biotech scale will lead to severaladvances. First, technology for large quantities of cells will be available for transplantation purposes. Second, CROs and Big Pharma will have large numbers of cells available for drug safety evaluation. An economically viable biotechnological process using readily available and inexpensive differentiation agents is needed. Herein, we propose to use a powerful combination of high content and high throughput cellular assays and dynamic medicinal chemistry to develop pure, easy to make, small molecule toolbox compounds to promote the induction of hESCs that will differentiate into cardiomyocytes. Promising cardiomyocyte differentiation agents (i.e., compounds 1-3) have been identified and refinement and development of these agents is the focus of this proposal. The Specific Aims include: 1) Test 740 structurally related compounds to 1-3 as inducers of cardiomyocytes in a validated human ESC assay and 2) Test compounds of Aim 1 in validated counterscreens to test for selectivity and mode of action of cardiomyocyte differentiation. Successful completion of the proposed work will provide an inexpensive toolbox of reagents useful for the induction of cardiomyocytes from human ESCs of widespread utility. PUBLIC HEALTH RELEVANCE: In the future, human stem cell therapy will provide a way to regenerate damaged heart muscle cells for heart attack victims. Current therapies only improve heart function and what is needed is the generation of new heart muscle cells. The goal of our work is to use chemical biologyto develop small molecule toolbox compounds that will stimulate stem cell differentiation and produce human cardiomyocytes. Ultimately, the results from this work will provide toolbox reagents for use to grow cardiomyocytes for use in a biotechnology process to treat heart disease and to improve the safety of human drugs in development.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 240.56K | Year: 2014

Project Summary/Abstract Developing new ways to treat pancreatic cancer is a significant challenge. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and results in an estimated 37,000 deaths/year. Pancreatic cancer therapeutic options are limited to surgery and/or combinations of chemotherapy and radiation. Unfortunately, late-stage diagnosis of pancreatic cancer renders current therapies ineffective. The effectiveness of relatively new targeted treatments remainsto be shown. There is an urgent major unmet medical need for the development of selective treatments for pancreatic cancer. Our new approach to pancreatic cancer is completely different and focuses on inhibition of a key molecular pathway. We have discovered and optimized a small molecule (i.e., 2) that selectively and potently inhibits a key molecular pathway. The overall Goal is to test this novel small molecule as an inhibitor to suppress pancreatic cancer progression by targeting a key signaling path


Schade D.,Human BioMolecular Research Institute | Schade D.,Sanford Burnham Institute for Medical Research | Schade D.,Chemregen, Inc. | Schade D.,TU Dortmund | And 13 more authors.
Journal of Medicinal Chemistry | Year: 2012

A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC 50s for TGFβ inhibition in the nanomolar range (e.g., compound 28, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (-) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells. © 2012 American Chemical Society. Source

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