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 treatments. The goal of the project is to develop small molecule inhibitors targeting small ubiquitin-like modifier-1 (SUMO1) as new anticancer drugs for glioblastoma treatment. SUMO1 is a small regulatory protein that is conjugated to other proteins through enzymatic reactions. Our recent studies have shown that SUMO1 conjugation is overactive in glioblastoma and drives the cancer progression. To target SUMO1 conjugation, we have developed glioblastoma cell-based SUMO1 conjugation assay in a drug screening of a NCI small molecules library and identified a hit compound SUMO1 inhibitor that we named as the SUMO1 inhibition compound (SMIC1). In examining the mode of action, we have shown that SUMO1 treatment induces the ubiquitination and degradation of SUMO1 protein and abolishes SUMO1 conjugation in glioblastoma. In pharmacokinetic (PK) testing, SMIC1 is quickly absorbed into circulation and distribution in brain through blood brain barrier (BBB). In pharmacodynamical (PD) and therapeutic testing, SMIC1 treatment significantly reduces SUMO1 protein in glioblastoma xenografts and increases the survival of glioblastoma xenograft mice without being toxic to mice. These studies indicate the potential of SMIC1 as a new anticancer drug for clinical treatment of glioblastoma. Before a new chemical entity can be used in clinic, however, it must go through a structure- activity relationship analysis of hit compound analogs to identify the chemical leads with improved potency and drug-like features. The process of understanding SAR for desired drug properties requires dozens of rounds of analog synthesis and biological analysis.
In Aim 1, we will first design and synthesize SMIC1 analogs through modifications of its chemical structures. The analogs will be tested by high-throughput cell growth and SUMO1 conjugation assay to identify the chemical leads with improved potency and aqueous solubility.
In Aim 2, the leads will be analyzed for the bioactivity and selectivity against cell growth and SUMO1 conjugation in a large panel of glioblastoma cell lines and the cancer stem cells-enriched neurospheres. The leads will be also tested for its toxicity, PK and BBB permeability in mice. These studies will select two of the leads with better safety and PK parameters and improved potency and BBB permeability for therapeutic testing in Aim 3. Glioblastoma cell line-derived mouse xenografts will be used for PD studies to determine if the leads inhibit SUMO1 proteins in glioblastoma xenografts. Glioblastoma 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 SMIC1. Upon completion, we expect to identify the chemical lead of SMIC1 with improved potency and drug-like features for drug development. This 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.
The objective of this SBIR phase I project is to develop small molecule inhibitors targeting small ubiquitin-like modifier-1 (SUMO1) as new anticancer drugs through medicinal chemistry for clinical treatment of the patients diagnosed with brain glioblastoma.