Phase I Amount
$1,019,583
Colorectal carcinoma (CRC) is the 4th most diagnosed cancer but the 2nd leading cause of cancer death mainly due to its metastatic disease (mCRC) in the liver and lungs. Currently there is no effective therapy available for patients diagnosed with mCRC. The ultimate goal of this project is to develop small-molecule degraders of small ubiquitin-related modifier 1 (SUMO1) as the first-in-class anticancer drugs for treatment of mCRC therapy. To achieve this goal, we have already identified a hit compound that selectively degrades SUMO1 protein in cancer but not normal cells. Structure-activity relationship (SAR) studies around the hit compound have generated our lead compounds with improved potency and drug-like properties. Using genetically defined CRC cell lines, 3- dimensional (3D) organoids and patient's derived xenografts (PDXs), we have shown that the lead compounds are more effective in treatment of mCRC than the current standard therapy. Our earlier work has focused on establishing a well-connected testing paradigm with sufficient capacity, including all the required in vitro and in vivo assays that has enabled identification and characterization of the current lead series. In this SBIR Phase II project, we will optimize our lead series with the aim to identify potent, selective and orally bioavailable SUMO1 degrader candidate(s). The candidate(s) will have the necessary preclinical efficacy, safety, and pharmacokinetic properties that predict it be enable full exploration of efficacy and safety in mCRC patients. In particular, Aim 1 will leverage our computational chemistry technology to assist the design of novel compounds through chemical modifications of the lead series. Each compound will be rationally designed, synthesized, and advanced through our established compound testing funnel. First, compounds will be screened using our high-capacity primary, secondary and counter-screen assays for their binding and target selectivity. Compounds that meet our criteria for success will be selected for in vitro solubility, permeability, absorption, distribution, metabolism, and excretion assessment and prioritized for the anticancer activity against CRC cell lines and 3D organoids. In Aim 2, the leading compounds selected from the studies of Aim 1 will be evaluated for their pharmacokinetic properties in rodents to determine clearance and oral bioavailability. Selected compound will be further assessed for in vivo target engagement and therapeutic efficacy using our mCRC PDX models after oral administration. Successful compounds will need to demonstrate an in vivo dose response target engagement with an adequate efficacious dose for translation into acceptable predicted human therapeutic dose and regimen. The optimized lead compounds through the studies in Aim 2 will be further evaluated for their toxicology, safety pharmacology, genotoxicity and oral bioavailability in dogs in Aim 3. The milestone of this project is to select the optimized lead compound(s) for advancement into preclinical development phase, investigative new drug-enabling studies and phase I clinical trials in treatment of patients diagnosed with mCRC, a deadly human disease.
Public Health Relevance Statement: Project Narrative The objective of this direct SBIR phase II project is to identify potent, selective and orally bioavailable small- molecule degraders of SUMO1 as novel anticancer drugs for treatment of patients diagnosed with metastatic colorectal carcinoma.
Project Terms: absorption; Oral Administration; Oral Drug Administration; intraoral drug delivery; Antineoplastic Agents; Anti-Cancer Agents; Antineoplastic Drugs; Antineoplastics; Cancer Drug; Neoplastic Disease Chemotherapeutic Agents; Tumor-Specific Treatment Agents; anti-cancer drug; anticancer agent; anticancer drug; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Biopsy; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; cell growth; Cellular Expansion; Cellular Growth; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Chemistry; Clinical Trials; Clone Cells; Large Intestine Carcinoma; Colo-rectal Carcinomas; Colorectal Carcinomas; Large Bowel Carcinoma; Cytochromes; Cessation of life; Death; Diagnosis; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Goals; Grant; Human; Modern Man; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Liver; hepatic body system; hepatic organ system; Lung; Lung Respiratory System; pulmonary; Metabolism; Intermediary Metabolism; Metabolic Processes; Mus; Mice; Mice Mammals; Murine; Nuclear Magnetic Resonance; Organoids; Patients; Permeability; Pharmacokinetics; Drug Kinetics; Pharmacology; Proteins; Rodentia; Rodents Mammals; Rodent; Safety; Solubility; Specificity; chemical structure function; structure function relationship; Structure-Activity Relationship; Technology; Testing; Toxicology; Translations; Ubiquitin; APF-1; ATP-Dependent Proteolysis Factor 1; HMG-20; High Mobility Protein 20; Work; Mediating; base; improved; Solid; Phase; Medical; Series; Chemicals; excretion; Excretory function; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; analog; Therapeutic; Metabolic; Malignant Cell; cancer cell; Oral; 3-D; 3D; three dimensional; 3-Dimensional; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; xeno-transplantation; Xenograft procedure; solid state; success; genotoxicity; novel; Modeling; Property; response; computational chemistry; Proteomics; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; cancer diagnosis; Molecular Interaction; Binding; Oncogenesis; tumorigenesis; small molecule; CUL1; Cullin 1; CUL1 gene; Dose; in vivo; Cancer Etiology; Cancer Cause; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Ubiquitination; Ubiquitilation; Ubiquitinoylation; ubiquination; ubiquitin conjugation; trend; Knock-out; Knockout; Modification; Development; developmental; ubiquitin ligase; Ubiquitin Ligase Component Gene; Ubiquitin Ligase Gene; metastatic colorectal; metastatic colo-rectal; metastatic colo-rectal cancer; metastatic colo-rectal carcinoma; metastatic colon cancer; metastatic colorectal cancer; metastatic colorectal carcinoma; computerized tools; computational tools; design; designing; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; Cancer cell line; anticancer activity; anti-cancer activity; human disease; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; effective therapy; effective treatment; genome-wide; genome scale; genomewide; counterscreen; preclinical efficacy; pre-clinical efficacy; preclinical safety; pre-clinical safety; preclinical toxicity; pre-clinical toxicity; lead series; Regimen; CRISPR/Cas technology; CRISPR approach; CRISPR based approach; CRISPR method; CRISPR methodology; CRISPR technique; CRISPR technology; CRISPR tools; CRISPR-CAS-9; CRISPR-based method; CRISPR-based technique; CRISPR-based technology; CRISPR-based tool; CRISPR/CAS approach; CRISPR/Cas method; CRISPR/Cas9; CRISPR/Cas9 technology; Cas nuclease technology; Clustered Regularly Interspaced Short Palindromic Repeats approach; Clustered Regularly Interspaced Short Palindromic Repeats method; Clustered Regularly Interspaced Short Palindromic Repeats methodology; Clustered Regularly Interspaced Short Palindromic Repeats technique; Clustered Regularly Interspaced Short Palindromic Repeats technology; Formulation; novel anticancer drug; new anti-cancer agent; new anticancer agent; new anticancer drug; new antineoplastic; new cancer drug; novel anti-cancer agent; novel anti-cancer drug; novel anticancer agent; novel antineoplastic; novel cancer drug; therapeutic biomarker; therapeutic marker; preclinical development; pre-clinical development; lead optimization; anti-cancer; anticancer; patient derived xenograft model; PDX model; Patient derived xenograft; rational design
