Development of Small Molecule SUMO1 Inhibitors for Treatment of Glioblastoma

Project Summary Abstract Glioblastoma is the most common and lethal brain cancer and the median survival of patients is less than a year due to the lack of effective glioblastoma targeted treatmentsThe goal of the project is to develop small molecule inhibitors targeting small ubiquitin like modifierSUMOas new anticancer drugs for glioblastoma treatmentSUMOis a small regulatory protein that is conjugated to other proteins through enzymatic reactionsOur recent studies have shown that SUMOconjugation is overactive in glioblastoma and drives the cancer progressionTo target SUMOconjugationwe have developed glioblastoma cell based SUMOconjugation assay in a drug screening of a NCI small molecules library and identified a hit compound SUMOinhibitor that we named as the SUMOinhibition compoundSMICIn examining the mode of actionwe have shown that SUMOtreatment induces the ubiquitination and degradation of SUMOprotein and abolishes SUMOconjugation in glioblastomaIn pharmacokineticPKtestingSMICis quickly absorbed into circulation and distribution in brain through blood brain barrierBBBIn pharmacodynamicalPDand therapeutic testingSMICtreatment significantly reduces SUMOprotein in glioblastoma xenografts and increases the survival of glioblastoma xenograft mice without being toxic to miceThese studies indicate the potential of SMICas a new anticancer drug for clinical treatment of glioblastomaBefore a new chemical entity can be used in clinichoweverit must go through a structureactivity relationship analysis of hit compound analogs to identify the chemical leads with improved potency and drug like featuresThe process of understanding SAR for desired drug properties requires dozens of rounds of analog synthesis and biological analysisIn Aimwe will first design and synthesize SMICanalogs through modifications of its chemical structuresThe analogs will be tested by high throughput cell growth and SUMOconjugation assay to identify the chemical leads with improved potency and aqueous solubilityIn Aimthe leads will be analyzed for the bioactivity and selectivity against cell growth and SUMOconjugation in a large panel of glioblastoma cell lines and the cancer stem cells enriched neurospheresThe leads will be also tested for its toxicityPK and BBB permeability in miceThese studies will select two of the leads with better safety and PK parameters and improved potency and BBB permeability for therapeutic testing in AimGlioblastoma cell line derived mouse xenografts will be used for PD studies to determine if the leads inhibit SUMOproteins in glioblastoma xenograftsGlioblastoma stem cells derived xenografts will be then tested to determine if the leads are more effective in treatment of glioblastoma as compared with the hit compound SMICUpon completionwe expect to identify the chemical lead of SMICwith improved potency and drug like features for drug developmentThis SBIR phase I studies will allow us to build up the foundation for entrance of SBIR phase II in which we will continue SAR studies to select a development candidate from potent and drugable leads as a new anticancer drug for phase I clinical trials in treatment of the patients diagnosed with glioblastoma Project Narrative The objective of this SBIR phase I project is to develop small molecule inhibitors targeting small ubiquitin like modifierSUMOas new anticancer drugs through medicinal chemistry for clinical treatment of the patients diagnosed with brain glioblastoma