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Willems E.,Sanford Burnham Institute for Medical Research | Willems E.,Chemregen, Inc. | Cabral-Teixeira J.,Sanford Burnham Institute for Medical Research | Schade D.,Sanford Burnham Institute for Medical Research | And 14 more authors.
Cell Stem Cell | Year: 2012

The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. To identify these signals, a mouse embryonic stem cell (ESC)-based differentiation assay was screened against a small molecule library resulting in a 1,4-dihydropyridine inducer of type II TGF-β receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively inhibiting intracellular signaling (IC50 ∼0.4-0.8 μM). ITD-1 was used to evaluate TGF-β involvement in mesoderm formation and cardiopoietic differentiation, which occur sequentially during early development, revealing an essential role in both processes in ESC cultures. ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. ITD-1 is a highly selective TGF-β inhibitor and reveals an unexpected role for TGF-β signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors. © 2012 Elsevier Inc.


Willems E.,Sanford Burnham Institute for Medical Research | Willems E.,Chemregen, Inc. | Spiering S.,Sanford Burnham Institute for Medical Research | Davidovics H.,Sanford Burnham Institute for Medical Research | And 8 more authors.
Circulation Research | Year: 2011

Rationale: Human embryonic stem cells can form cardiomyocytes when cultured under differentiation conditions. Although the initiating step of mesoderm formation is well characterized, the subsequent steps that promote for cardiac lineages are poorly understood and limit the yield of cardiomyocytes. Objective: Our aim was to develop a human embryonic stem cell-based high-content screening assay to discover small molecules that drive cardiogenic differentiation after mesoderm is established to improve our understanding of the biology involved. Screening of libraries of small-molecule pathway modulators was predicted to provide insight into the cellular proteins and signaling pathways that control stem cell cardiogenesis. Methods and Results: Approximately 550 known pathway modulators were screened in a high-content screening assay, with hits being called out by the appearance of a red fluorescent protein driven by the promoter of the cardiac-specific MYH6 gene. One potent small molecule was identified that inhibits transduction of the canonical Wnt response within the cell, which demonstrated that Wnt inhibition alone was sufficient to generate cardiomyocytes from human embryonic stem cell-derived mesoderm cells. Transcriptional profiling of inhibitor-treated compared with vehicle-treated samples further indicated that inhibition of Wnt does not induce other mesoderm lineages. Notably, several other Wnt inhibitors were very efficient in inducing cardiogenesis, including a molecule that prevents Wnts from being secreted by the cell, which confirmed that Wnt inhibition was the relevant biological activity. Conclusions: Pharmacological inhibition of Wnt signaling is sufficient to drive human mesoderm cells to form cardiomyocytes; this could yield novel tools for the benefit of pharmaceutical and clinical applications. © 2011 American Heart Association, Inc.


Lanier M.,Human BioMolecular Research Institute | Lanier M.,Chemregen, Inc. | Schade D.,Human BioMolecular Research Institute | Schade D.,Sanford Burnham Institute for Medical Research | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2012

Human embryonic stem cell-based high-content screening of 550 known signal transduction modulators showed that one "lead" (1, a recently described inhibitor of the proteolytic degradation of Axin) stimulated cardiomyogenesis. Because Axin controls canonical Wnt signaling, we conducted an investigation to determine whether the cardiogenic activity of 1 is Wnt-dependent, and we developed a structure-activity relationship to optimize the cardiogenic properties of 1. We prepared analogues with a range of potencies (low nanomolar to inactive) for Wnt/β-catenin inhibition and for cardiogenic induction. Both functional activities correlated positively (r 2 = 0.72). The optimal compounds induced cardiogenesis 1.5-fold greater than 1 at 30-fold lower concentrations. In contrast, no correlation was observed for cardiogenesis and modulation of transforming growth factor β (TGFβ)/Smad signaling that prominently influences cardiogenesis. Taken together, these data show that Wnt signaling inhibition is essential for cardiogenic activity and that the pathway can be targeted for the design of druglike cardiogenic molecules. © 2011 American Chemical Society.


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.


Willems E.,Sanford Burnham Institute for Medical Research | Willems E.,Chemregen, Inc. | Lanier M.,Human BioMolecular Research Institute | Lanier M.,Chemregen, Inc. | And 7 more authors.
Journal of Cardiovascular Translational Research | Year: 2011

Heart failure is one of the major causes of death in the Western world because cardiac muscle loss is largely irreversible and can lead to a relentless decline in cardiac function. Novel therapies are needed since the only therapy to effectively replace lost myocytes today is transplantation of the entire heart. The advent of embryonic and induced pluripotent stem cell (ESC/iPSC) technologies offers the unprecedented possibility of devising cell replacement therapies for numerous degenerative disorders. Not only are ESCs and iPSCs a plausible source of cardiomyocytes in vitro for transplantation, they are also useful tools to elucidate the biology of stem cells that reside in the adult heart and define signaling molecules that might enhance the limited regenerative capability of the adult human heart. Here, we review the extracellular factors that control stem cell cardiomyogenesis and describe new approaches that combine embryology with stem cell biology to discover drug-like small molecules that stimulate cardiogenesis and potentially contribute to the development of pharmaceutical strategies for heart muscle regeneration. © Springer Science+Business Media, LLC 2011.


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


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


Chemregen, Inc. | Entity website

ChemRegen, Inc. is a privately held regenerative medicine research and development corporation located in San Diego, California ...


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.

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