# SUMO1 inhibition compound as a new anticancer drug for glioblastoma therapy

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $379,607

## Abstract

Our ultimate goal is to develop novel and effective treatments of glioblastoma, the most common and lethal
human brain cancer. To achieve this goal, we propose to develop the SUMO1 inhibition compound (SMIC1) as
a new anticancer drug for glioblastoma therapy. SUMO1 (small ubiquitin-like modifier-1) is a small regulatory
protein that is linked to substrate proteins through enzymatic reactions. SUMO1 conjugation of its substrate
proteins controls the cellular function of substrate proteins. In our recent work, we have revealed that SUMO1
conjugation pathway is overactive in glioblastoma and drives the cancer progression. To target this pathway,
we have developed glioblastoma cell-based SUMO1 assays for drug screening and identified the SMIC1 from
the NCI drugable compound library. In the efforts of preclinical development of SMIC1 as an anticancer drug,
we have followed the FDA guidance for nonclinical evaluation of new anticancer agents and tested the toxicity
and pharmacokinetics (PK) of SMIC1 and demonstrated that SMIC1 has an acceptable safety margin and
drugable PK features in animals. In systemic administration, SMIC1 can be quickly delivered to brains through
the blood brain barrier (BBB) and effectively inhibits glioblastoma xenograft growth.
In search of target proteins, we have shown that cyclin-dependent kinase-6 (CDK6) is a substrate of both
SUMO1 and ubiquitin (UB). SUMO1-CDK6 conjugation blocks CDK6 ubiquitination and the UB-mediated
degradation and thus stabilizes CDK6 kinase for driving cell growth through phosphorylation of retinoblastoma
protein-1 (RB1); thus, SMIC1 treatment blocks SUMO1-CDK6 conjugation and eliminates CDK6-RB1 pathway.
On the other hand, CDK4/6 inhibitors have been developed targeting CDK4/6-RB1 pathway and they are now
in clinic for cancer therapies. RB1 deletion and mutation occurs in about 11% glioblastomas and results in the
cancer resistance to CDK4/6 inhibitors. In contrast, we have shown that SMIC1 can overcome the resistance
through inhibition of various SUMO1 substrate proteins. The objective of this proposal is to develop SMIC1 as
a new anticancer drug for treatment of glioblastomas. To achieve this, we will first determine the molecular
mechanisms of action of SMIC1 in treatment of glioblastoma cells. In particular, we will examine how SMIC1
treatment induces the ubiquitination and degradation of SUMO1 protein and abolishes SUMO1 conjugation
pathway in human glioblastoma cells. Next, we will examine the bioactivity and pharmacodynamics of SMIC1
in comparison with CDK4/6 inhibitors in genetically heterogenous glioblastoma cells and thus determine why
SMIC1 treatment can overcome the resistance of RB1 deletion and mutation. Finally, we will evaluate the
therapeutic efficacy of SMIC1 using the cancer stem cell cultures and xenograft models generated from
patients' glioblastoma tissues. Upon completion, this project will lead to the genesis of a new class anticancer
drug for clinical treatment of glioblas...

## Key facts

- **NIH application ID:** 9828082
- **Project number:** 5R01CA203893-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** CHUNHAI Charlie HAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,607
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828082

## Citation

> US National Institutes of Health, RePORTER application 9828082, SUMO1 inhibition compound as a new anticancer drug for glioblastoma therapy (5R01CA203893-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828082. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*