# Development of BBB-permeable SUMO1 small molecule degraders for glioblastoma therapy.

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $445,738

## Abstract

Project Summary/Abstract
Glioblastoma (GBM) is the most common and lethal primary brain tumor with the median survival of 9.7 months.
The current standard of care treatment involves a combination of surgery, chemotherapy and radiation but only
improve the median survival up to 14 months. Challenges in discovery of therapeutics for GBM include identifying
drug targets and discovering therapeutics that are blood brain barrier (BBB) permeable. To meet the challenges,
we have identified small ubiquitin-related modifier 1 (SUMO1) as an oncoprotein that drives the self-renewal and
tumorigenesis of GBM stem cells. We have designed GBM cell-based SUMO1 assay, screened the compounds
library provided by the National Cancer Institute, and identified the hit compound as the first small molecule
degrader that induces SUMO1 ubiquitination and degradation in GBM cells. Structure-activity relationship (SAR)
studies around the hit-derived analogs have generated three scaffolds of lead compounds with improved potency
and an excellent BBB permeability. Using GBM stem cell-enriched neurospheres and derived xenografts, we
have shown that the lead compounds are more effective in treatment of GBM than the standard chemotherapy
temozolomide (TMZ). In this R01 project, we will optimize our lead series with the aim of identifying more potent,
orally bioavailable and BBB-permeable SUMO1 degraders that will have the preclinical efficacy, safety, and
pharmacokinetic properties predicting it be enable full exploration in clinical treatment of GBM. To achieve this
objective, we will leverage our computational chemistry technology to assist the design of novel compounds with
BBB permeability and drug-like properties through chemical modifications of our lead series in Aim 1. Each of
compounds will be rationally designed, synthesized and assessed in our established compound testing funnel
for their activity and target selectivity in SUMO1 degradation. 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 GBM stem cell-enriched neurospheres. In Aim 2, the leading
compounds selected from the studies of Aim 1 will be evaluated for their pharmacokinetic properties to determine
oral bioavailability and BBB permeability. Selected compounds will be assessed for in vivo target engagement
and therapeutic efficacy in treatment of patient derived xenograft GBM models. The optimized lead compounds
selected from the studies in Aim 2 will be evaluated for their toxicology, safety pharmacology and oral formulation
in Aim 3. The milestone of this project is to select optimized lead compound(s) for advancement into preclinical
development phase, investigative new drug-enabling studies and phase I trials in treatment of GMB patients.

## Key facts

- **NIH application ID:** 10791776
- **Project number:** 5R01NS126358-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** CHUNHAI Charlie HAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,738
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791776

## Citation

> US National Institutes of Health, RePORTER application 10791776, Development of BBB-permeable SUMO1 small molecule degraders for glioblastoma therapy. (5R01NS126358-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10791776. Licensed CC0.

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