Project Summary/Abstract 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 s...