SBIR-STTR Award

Development of Small Molecule Sumo1 Inhibitors for Treatment of Glioblastoma
Award last edited on: 3/5/19

Sponsored Program
SBIR
Awarding Agency
NIH : NCI
Total Award Amount
$300,000
Award Phase
1
Solicitation Topic Code
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Principal Investigator
Anita Bellail

Company Information

HB Therapeutics Inc

1800 North Capitol Avenue Suite E504
Indianapolis, IN 46202
   (313) 205-6731
   N/A
   www.hbtpx.com
Location: Single
Congr. District: 07
County: Marion

Phase I

Contract Number: 1R43CA224461-01A1
Start Date: 7/6/18    Completed: 6/30/19
Phase I year
2018
Phase I Amount
$300,000
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.

Project Terms:
Amino Acids; analog; Antineoplastic Agents; aqueous; base; benzothiazole; Biochemical Reaction; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Glioblastoma; Cancer Patient; cancer stem cell; cell growth; Cell Line; Cells; Chemical Structure; Chemicals; Clinic; Clinical Treatment; commercialization; design; Development; Diagnosis; Diffuse; drug development; drug discovery; Drug Kinetics; Drug Screening; Evaluation; Foundations; genetic regulatory protein; Glioblastoma; Goals; Growth; Guidelines; improved; Infiltration; inhibitor/antagonist; Lead; Libraries; Malignant - descriptor; Malignant neoplasm of brain; Malignant Neoplasms; Maximum Tolerated Dose; Modification; Mus; Names; Nitriles; No-Observed-Adverse-Effect Level; novel anticancer drug; novel therapeutics; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; pharmacophore; Pharmacotherapy; Phase; phase 1 study; Phase I Clinical Trials; Post-Translational Protein Processing; Process; Property; Protein Isoforms; Proteins; Radiation; Safety; screening; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; small molecule libraries; Solubility; standard care; Stem cells; Structure; Structure-Activity Relationship; Survival Analysis; targeted treatment; temozolomide; Testing; therapeutic evaluation; Time; Toxic effect; Toxicity Tests; Toxicology; Treatment Efficacy; tumor progression; Ubiquitin; Ubiquitin family; Ubiquitination; Urea; Xenograft procedure;

Phase II

Contract Number: ----------
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
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Phase II Amount
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