MIAMI, FL, United States

Stemsynergy Therapeutics, Inc.

www.stemsynergy.com
MIAMI, FL, United States
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Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.


Li B.,University of Miami | Fei D.L.,University of Miami | Flaveny C.A.,University of Miami | Dahmane N.,University of Pennsylvania | And 12 more authors.
Cancer Research | Year: 2014

The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. © 2014 American Association for Cancer Research.


Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.97K | Year: 2016

DESCRIPTION provided by applicant Triple negative breast cancer TNBC represents an aggressive tumor type with a distinct lack of effective treatment options Standard of care chemotherapy regimens typically produce a partial response followed by regression months to years later This Phase I application tests the hypothesis that in subtypes of TNBC activation of the WNT pathway represents the underlying mechanism of resistance to chemotherapy Subsets of TNBC patients demonstrate high levels of LRP which correlates with activated WNT signaling and poor prognosis Over the past years a clear link has been established between breast cancer stem cells and activated WNT signaling Cells that are not affected by chemotherapy often exhibit activated WNT signaling However the distinct lack of effective WNT inhibitors has slowed the translation of these discoveries into patients No WNT inhibitors are available in the clinic We have developed a monoclonal antibody that targets LRP a co receptor in the canonical WNT pathway The initial mouse IgG antibody SST mAb demonstrates significant in vitro and in vivo activity to inhibit the WNT pathway Based on these studies in order to facilitate clinical development we have developed a human chimeric version SST mAb that potently inhibits WNT signaling in a TNBC cell line SST mAb targets the hinge region of the extracellular domain of LRP which is unique from other approaches by pharma biotech to target LRP Additionally SST mAb specifically targets canonical WNT activation unlike other pan WNT inhibitors currently in early clinical trials This SBIR Phase I application proposal is designed to initially evaluate SST mAbandapos s in vitro potency in inhibiting the growth of TNBC cell lines with elevated LRP as well assess SST mAbandapos s efficacy in established cancer stem cell assays We will perform subsequent studies to evaluate SST mAbandapos s in vivo efficacy as monotherapy and in combination with standard of care drugs currently used for treating TNBC Targeted biologics have the distinct advantage of exhibiting specificity for the target while minimizing off target toxicities Our overall goal and development approach uses an established model for a streamlined progression through to clinical trials Successful completion of these Phase I aims represents critical steps toward those goals PUBLIC HEALTH RELEVANCE The discovery of a therapeutic to effectively treat triple negative breast cancer TNBC would represent a major breakthrough in cancer research This application outlines the next steps in the evaluation a unique monoclonal antibody that targets subsets of TNBC patients that have high levels of WNT signaling Successful completion of these aims will allow us to progress this technology closer to proof of concept in the clinic


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

ABSTRACT Burns represent one of the most traumatic and debilitating injuries affecting over million people in the United States Reparative processes occurring after acute burn injury ultimately result in fibrosis scarring In experimental systems WNT pathway activation promotes scarring while inhibition leads to regeneration We have identified pyrvinium SST an FDA approved anthelminthic drug as a potent inhibitor of WNT signaling Our preliminary studies in mouse wound models indicate that topical delivery of SST promotes regenerative wound healing increased tensile strength and reduced fibrosis after cutaneous injury The goal of this Phase I proposal is a concerted effort between StemSynergy Therapeutics Inc SSTI and Vanderbilt University to evaluate a novel class of small molecule CK agonists that promote regenerative healing reduced scarring of burn injuries with improved efficacy compared to SST Preliminary topical formulation and efficacy studies involving SSTI s lead CK agonists will be assessed in two well established animal models of regenerative healing Successful completion of these studies will allow us to evaluate and prioritize our CK agonists for more comprehensive formulation and efficacy studies in a Phase II application NARRATIVE The development of new therapies that reduce scar tissue formation following burn injuries has been a major challenge Herein we present the development of a new first in class therapeutic for treating burns that promotes regenerative healing over scar tissue The market and benefit to society for the successful development of this product is enormous


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 140.00K | Year: 2010

DESCRIPTION (provided by applicant): StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. The World Health Organization estimates that over 12 million cases of cancer were diagnosed in 2007 and that nearly 8 million cancer patients will die of their disease. Colorectal cancer represents the second most common cause of death due to cancer with 1.2 million deaths. Activating mutations in the Wnt signaling pathway are the earliest events in the genesis of colorectal cancer, and, remarkably, are present in over 90% of all cases. There is an urgent need for inhibitors of the Wnt pathway for the treatment of colorectal cancer and other Wnt-driven cancers. Currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. SSTI has developed a powerful biochemical screen to identify Wnt inhibitors utilizing two independent readouts of the Wnt pathway. By assessing the stability of two Wnt pathway proteins, 2-catenin and Axin, SSTI has screened and identified an FDA-approved compound (SST-024) that potently inhibits Wnt signaling (EC50~10 nM). SST-024 was previously approved for a non-cancer indication. Our studies of SST-024 indicate that it is also a potent inhibitor of colorectal cancer cell growth and viability. Importantly, SST-024 is 80 times more selective in inhibiting the growth of a colorectal cancer cell line with an activating mutation in the Wnt pathway (human SW480 cells) compared to a genetically identical cancer line that has wild-type APC restored (human SW480APC cells). Due to intellectual property issues (SST-024 is off- patent) and concerns about bioavailability, we embarked on a virtual screening approach to identify compounds with improved bioavailability and drug-like properties. One of our lead compounds from this screen, SST-163, potently inhibits Wnt signaling and blocks the growth of Wnt-driven cancer cell lines. SST-163 also selectively inhibits the growth of SW480 cells over SW480APC cells which would correlate with a therapeutic window for the treatment of cancer cells over normal tissue. We have subsequently shown in vivo efficacy using SST-163 to block the growth of human SW480 cells in a mouse xenograft model. Based on these studies, we initiated a medicinal chemistry program focused on the synthesis of SST-163 analogs that further optimized their drug-like properties. Currently, our lead optimization efforts have generated a library of more water soluble derivatives for further evaluation. As part of our initial preclinical characterization of the SST-163 class of Wnt inhibitors, we propose to test our SST-163-based library for potency against the Wnt pathway, for favorable toxicology profiles, and for bioavailability models. The most promising compounds identified in these studies will be tested for their efficacy on a series of human colorectal cancer lines that harbor activating Wnt mutations as well as mutations in other signaling pathways in order to identify the subset of patients for whom our compounds may be the most efficacious. Finally, we propose to perform studies using promising SST-163 derivatives to identify pharmacologically relevant markers for the status of Wnt signaling. Because there are no drugs on the market that target the Wnt pathway, SSTI has the potential to improve and prolong the lives of millions of cancer patients worldwide. In summary, SSTI has the opportunity to bring to the market the first generation of Wnt inhibitors and capture a significant share of the global market for cancer drugs. PUBLIC HEALTH RELEVANCE: Colorectal cancer is responsible for 1.2 million cases and 650,000 deaths each year. The Wnt pathway is a major growth pathway that plays a critical role in gt90% of all cases and there are currently no inhibitors in the clinic. We intend to develop our lead compound Wnt pathway inhibitors through pre-clinical and clinical trials for a treatment of colorectal cancer.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.00M | Year: 2012

DESCRIPTION (provided by applicant): StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. The WorldHealth Organization estimates that over 12 million cases of cancer were diagnosed in 2007 and that nearly 8 million cancer patients will die of their disease. Colorectal cancer (CRC) represents the third most common cause of death due to cancer with 610,000 deaths. Activating mutations in the Wnt signaling pathway are the earliest events in the genesis of CRC, and, remarkably, are present in over 90% of all cases. There is an urgent need for inhibitors of the Wnt pathway for the treatment of colorectal cancer and other Wnt- driven cancers. Currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. SSTI has developed a powerful biochemical screen to identify Wnt inhibitors utilizing two independent readouts ofthe Wnt pathway. By assessing the stability of two Wnt pathway proteins, 2-catenin and Axin in a high- throughput screen, SSTI has identified small molecules that regulate Wnt signaling via activation of Casein Kinase 1a. Using a novel approach to lead optimization, SSTI has developed a new series of lead compounds that have more drug-like properties. Our successful Phase I SBIR project demonstrated that these compounds potently inhibit Wnt signaling, decrease the viability of a variety of human CRC cell lines, have good ADMET properties, and show in vivo efficacy. Additionally, SSTI was able to develop a secondary (backup series) using medicinal chemistry. Both classes of small molecules represent new chemical entities and our Phase II application outlinesthe next logical steps in their development by optimizing metabolism, demonstrating efficacy and performing safety studies in rodent and non-rodent. Our overall goal of this Phase II project is to demonstrate all of the necessary properties for IND submission according to the FDA guidance (ICH S9) for clinical trials of advanced colorectal cancer. Because there are no drugs on the market that target the Wnt pathway, SSTI has the potential to improve and prolong the lives of millions of cancer patients worldwide. In summary, SSTI has the opportunity to bring to the market the first generation of Wnt inhibitors and capture a significant share of the global market for cancer drugs. PUBLIC HEALTH RELEVANCE: Colorectal cancer is responsible for 1.2 million cases and 610,000 deaths each year. The Wnt pathway is a major growth pathway that plays a critical role in gt90% of all cases and there are currently no inhibitors in the clinic. We intend to develop our lead compound Wnt pathway inhibitors through pre-clinical and clinical trials for a treatment of colorectal cancer.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 259.45K | Year: 2012

DESCRIPTION (provided by applicant): Despite significant advancements in modern medicine with regards to surgery, radiation therapy and imaging of tumors, the survival rate for patients with non-small-cell lung carcinoma (NSCLC) remain almost identical to20 years ago. Current therapies targeting the proliferative mechanisms of NSCLC cancers such as K-RAS and EGFR have been the focus of a large effort in the pharmaceutical industry and academic laboratories. Such therapies have benefits over classical chemotherapy agents in prolonging median progression-free survival but have almost no effect on overall survival. In recent years, it has become clear that cancers are highly heterogeneous and the initial sensitivity to chemotherapy is the effect on the more differentiated (highly proliferative) cell types. The cancer stem cell population distributed within the initial tumor mass is resistant to chemotherapy and displays a highly invasive/metastatic phenotype. StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. Recent high profile literature studies have shown that cancer stem cell populations in NSCLC demonstrate aberrant Wnt pathway activity are sensitive to secreted Wnt inhibitors. There is an urgent need for inhibitors of the Wnt pathway because currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. This application describes the discovery and development of a new class of Wnt pathway inhibitors that activate Casein Kinase 1a (CK1a). Additional to the highly potent Wnt inhibitory activity, these small molecules activate p53. StemSynergy aims to develop atreatment for NSCLC that synergizes with current FDA approved drugs for NSCLC by targeting the drug resistant cells/cancer stem cells to eliminate ALL cancer cells and therefore increase survival for lung cancer patients. PUBLIC HEALTH RELEVANCE:Lung cancer is the largest cause of mortality and morbidity with 1.4 million deaths per year worldwide. StemStynergy is developing Wnt inhibitors to target the drug resistant cancer stem cell population to decrease metastasis and increase overall survival.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 224.99K | Year: 2016

DESCRIPTION provided by applicant The tumor suppressor Adenomatous Polyposis Coli APC directs degradation of catenin a central signaling protein in the WNT pathway Germline loss of function mutations in APC activate WNT signaling and underlie the inherited colorectal cancer predisposition syndrome Familial Adenomatous Polyposis FAP an orphan disease while somatic mutations lead to sporadic colorectal cancer CRC Current treatment for FAP includes colectomy as well as relatively ineffective medical management aimed at inhibiting further polyp formation Thus there is a compelling unmet need for effective medical therapies for patients with FAP with effective therapies also having potential for chemoprevention against sporadic CRC as well We have demonstrated that pyrvinium an FDA approved antihelminthic drug attenuates WNT signaling Within we show that pyrvinium inhibits polyp formation in the intestinal epithelium of a mutant APC driven mouse model for FAP APC min mice via attenuation of WNT signaling We hypothesize that pyrvinium driven inhibition of WNT signaling will improve survival in FAP We propose preclinical studies enabling us to repurpose pyrvinium through the orphan drug program to treat FAP patients Because FAP patients will be taking pyrvinium chronically we will identify the minimum dose of pyrvinium required to attenuate WNT signaling in FAP mice We will then treat cohorts of FAP mice monitoring responses including survival intestinal pathology and WNT biomarkers in short and long term treatments Successful completion enables us to complete requirements to file for Orphan Drug Designation for pyrvinium PUBLIC HEALTH RELEVANCE Familial Adenomatous Polyposis is a precancerous disease driven by WNT signaling that occurs in young adults with no effective treatment options Patients develop hundreds of polyps in their colon and subsequently require the removal of their colon We propose to develop a Wnt Inhibitor pyrvinium under the orphan drug program to treat this disease


Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.

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