c-Myc- and KRas-dependent cancers, such as colorectal cancer, represent major unmet medical needs that currently lack targeted therapy. Recent scientific advances revealed that these undruggable oncogenes critically depend on post-translational modification with the small ubiquitin-like modifier (SUMO) family of proteins, and inhibiting SUMOylation inhibits c-Myc and KRas. Furthermore, SUMOylation inhibition can activate anti-tumor immune responses. Genome- wide gene expression analysis has demonstrated that the SUMO activating enzyme (E1) is the most overexpressed SUMOylation-related protein in colorectal cancers tissues. SUMO E1 overexpression is also associated with cancer cell stemness and poor patient survival. This evidence makes SUMO E1 an attractive target. Therefore, we propose to develop highly selective, potent, and orally available SUMO E1 inhibitors as targeted therapies for colorectal cancer. Using a high-throughput screening campaign, we have identified a class of potent and specific SUMO E1 inhibitors suitable for development into orally available drugs, which could represent a new class of therapeutic agents. We will conduct lead optimization of these compounds and validate the resulting candidates in cellular assays of colorectal cancer, followed by pharmacokinetic and toxicity studies. In addition to colorectal cancer, which is the focus of our proposal, inhibiting SUMOylation will likely inhibit other c-Myc and KRas-dependent cancers. Thus, the potent SUMO E1 inhibitors developed in the proposed studies are expected to have a major impact on cancer research and targeted therapy.
Public Health Relevance Statement: We propose to develop an orally available SUMO E1 inhibitor for cancer therapy.
Project Terms: Address; Animal Model; anti-tumor immune response; anticancer research; base; Biological Availability; c-myc Genes; cancer cell; Cancer Patient; cancer survival; cancer therapy; cancer type; CD47 gene; Cell Line; Cell model; Cells; Cellular Assay; Characteristics; chemical synthesis; clinical development; colon cancer cell line; Colorectal Cancer; colorectal cancer treatment; commercialization; Development; Drug Industry; Drug Kinetics; drug metabolism; Drug Targeting; Enzyme Inhibitor Drugs; Enzymes; FDA approved; Formulation; Funding; Future; Gene Expression Profiling; Genes; genome-wide; Goals; high throughput screening; Immune response; improved; In Vitro; in vivo; inhibitor/antagonist; innovation; insight; interest; Knowledge; Lead; lead optimization; Letters; Literature; Malignant Neoplasms; Medical; Modification; Molecular Abnormality; Mus; MYC gene; new therapeutic target; novel; Oncogenes; Oral; overexpression; Pathway interactions; Patients; PDCD1LG1 gene; Pharmaceutical Preparations; Phase; phase 2 study; Post-Translational Protein Processing; programs; Property; Protein Family; Proteins; Resources; Safety; scale up; Scheme; Scientific Advances and Accomplishments; Small Business Innovation Research Grant; small molecule inhibitor; Specificity; stemness; targeted treatment; Testing; Therapeutic; Therapeutic Agents; Therapeutic Studies; Tissues; Toxic effect; Toxicology; Translating; Tumor Immunity; Ubiquitin
