SBIR-STTR Award

The leading commercial goal of our company is to develop novel therapeutics to inhibit the human oncogene, c-Myc. C-Myc is a major human oncogene that is estimated to contribute to at least 70% of all human cancers, most of which are aggressive and respond poorly to current therapies. Despite more than 30 years of research, the development of drugs that inhibit c-Myc has been unsuccessful because the protein is a transcription factor that lacks pockets for small molecules to bind. Therefore, developing novel treatments that inhibit c-Myc is considered one of the most important goals for advancing cancer therapeutics. Recently studies from several laboratories including ours have shown that the small ubiquitin-like modifications (SUMO) are critical for c-Myc-dependent tumorigenesis. Our initial studies are focused on colorectal cancers, because these cancers are almost 100% dependent on c-Myc and new therapies are critically needed for metastatic colorectal cancers to improve patient survival. SUMOylation is important for c-Myc expression through activation of beta-catenin/Tcf-4, the transcription factor for c-Myc expression in colorectal cancers. In preliminary studies, we have identified a very specific and potent inhibitor scaffold of SAE, the activating enzyme that catalyzes SUMO modifications, using high throughput screening. Inhibition of SUMOylation with this inhibitor or by knockdown of SAE dramatically reduced c-Myc level in colorectal cancer cells. We have designed strategies to improve the potency of the lead compound based on our recent discovery of its novel mechanism of action, which indicates a tractable approach to increase its specificity, potency and duration of action. We will then determine the specificity and cellular mechanisms of the improved compounds and will conduct toxicity and efficacy studies in animal models. Our results will significantly advance the field byproviding the first proof-of-concept in animal models that SUMOylation is a potential target to inhibit the c-Myc oncogene.

Thesaurus Terms:
Address;Advanced Malignant Neoplasm;Animal Model;Base;Beta Catenin;Binding (Molecular Function);Biochemical;C-Myc Genes;Cancer Cell;Cancer Cell Line;Cancer Therapy;Cell Death;Cell Line;Cells;Cellular Assay;Chemical Synthesis;Clinical;Colorectal Cancer;Design;Development;Disease;Dose;Drug Formulations;Drug Industry;Drug Kinetics;Drug Metabolism;Effective Therapy;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Funding;Future;Goals;Growth;High Throughput Screening;Human;Improved;In Vitro;In Vivo;Inhibitor/Antagonist;Interest;Killings;Laboratories;Lead;Letters;Libraries;Life;Malignant Neoplasms;Medical;Metastatic Colorectal;Modification;Mouse Model;Myc Gene;Neoplasm Metastasis;Normal Cell;Normal Tissue Morphology;Novel;Novel Therapeutics;Oncogenes;Oncology;Pathway Interactions;Patients;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Phase 2 Study;Programs;Property;Proteins;Public Health Relevance;Research;Research And Development;Rodent;Scaffold;Scale Up;Small Business Innovation Research Grant;Small Molecule;Specificity;Study Section;Therapeutic;Therapeutic Development;Therapeutic Target;Three Dimensional Structure;Tissues;Toxic Effect;Toxicology;Transcription Factor;Tumorigenesis;Ubiquitin;Xenograft Procedure;

The main commercial goal of our company is to develop novel therapeutics to inhibit the human oncogene, c-Myc. C-Myc is a major human oncogene that is estimated to contribute to at least 70% of all human cancers, most of which are aggressive and respond poorly to current therapies. Despite more than 30 years of research on c-Myc, the development of drugs that inhibit c-Myc has been unsuccessful because the protein is a transcription factor that lacks pockets for small molecules to bind. Therefore, developing novel treatments that inhibit c-Myc is considered one of the most important goals for advancing cancer therapeutics. Recently studies from several laboratories, including ours, have shown that the small ubiquitin-like modifications (SUMO) are critical for c-Myc- dependent tumorigenesis. Therefore, our research has focused on inhibiting c-Myc by targeting SUMOylation. Our initial studies are focused on colorectal cancers, because nearly 100% of these cancers depend on c-Myc, and new therapies are critically needed for metastatic colorectal cancers to improve patient survival. SUMOylation is important for c-Myc expression by activating ß- catenin/Tcf-4, the key transcription factor for inducing c-Myc expression in colorectal cancers. We have successfully completed the studies proposed for our Phase I SBIR award and have developed a new series of lead compounds that have improved potency and specificity. In Phase II studies, we propose to conduct necessary pharmacology formulation development, Chemistry, Manufacturing and Controls work, and IND-enabling studies. At the completion of these preclinical Phase II studies we anticipate being prepared to file an IND application to support further progress toward clinical trials. Ultimately, development of effective c-Myc-inhibiting drug would be paradigm-shifting for cancer treatment and fill a major void in the market.

Public Health Relevance Statement:


Public Health Relevance:
The overall goal is to produce highly potent and specific SUMO activating enzyme inhibitor to treat c-Myc-dependent.

NIH Spending Category:
Biotechnology; Cancer; Colo-Rectal Cancer; Digestive Diseases

Project Terms:
Address; Advanced Malignant Neoplasm; Animal Model; Animals; anti-cancer therapeutic; Area; Award; beta catenin; Binding (Molecular Function); Binding Sites; Biological Markers; Bortezomib; c-myc Genes; cancer therapy; Canis familiaris; Cell Line; Chemistry; Clinical; Clinical Trials; colon cancer cell line; Colorectal Cancer; cytotoxic; design; Development; Dose; drug development; Drug Formulations; Drug Industry; Drug Kinetics; drug metabolism; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; FDA approved; Funding; Future; Generations; Goals; Growth; Guidelines; Human; improved; inhibitor/antagonist; interest; intravenous injection; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; lead series; Letters; Malignant Neoplasms; Marketing; Medical; Metabolic; metastatic colorectal; model development; Modification; mouse model; MYC gene; Names; Neoplasm Metastasis; Normal tissue morphology; novel; novel therapeutics; Oncogenes; Patients; Pharmaceutical Preparations; Pharmacology; Phase; phase 1 study; phase 2 study; pre-clinical; programs; Proteasome Inhibitor; Proteins; public health relevance; Rattus; Research; Resistance; Rodent; Small Business Innovation Research Grant; small molecule; Specificity; success; Therapeutic; Toxic effect; Toxicology; Trans-Activation (Genetics); transcription factor; Tumor Tissue; tumorigenesis; Ubiquitin; United States National Institutes of Health; Work; Xenograft procedure