# Irreversible Inhibtion of Cerebellar Gli Transcription Factors by Cobalt (III) Complexes

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2021 · $40,860

## Abstract

Aberrant expression of the Hedgehog (Hh) signaling pathway is heavily implicated in the formation and
proliferation of a subgroup of medulloblastoma (MB) tumors. MB is predominantly a pediatric brain cancer, with
70% of occurrences appearing in children under the age of 10. The SHH subgroup, driven by Hh signaling, is
widely heterogeneous in genetic cause and histology, making effective treatment challenging and resulting in
dismal outcomes. Current treatment strategies involve tumor resection, craniospinal irradiation, and
chemotherapy, but suffer from short-term and long-term adverse effects. In efforts to inhibit the Hh pathway,
research has targeted the protein Smoothened (Smo), but has been stunted by downstream mutations that
lead to cancer recurrence with a much higher lethality. Thus, this project seeks to target Gli proteins, which
belong to a family of zinc finger transcription factors (TFs) and are the final effectors of the Hh pathway. The
Meade lab has developed a series of Cobalt (III)-Schiff base complexes (Co(III)-sb) coupled to TF consensus
sequences that specifically and irreversibly inhibit zinc finger TFs of interest. This proposal seeks to reinvent
the method for conjugating Co(III)-sb to the Gli consensus sequence to generate Co(III)-Gli, a highly specific
and irreversible inhibitor of Gli proteins. This inhibitor will be conjugated to a Gd(III)-labeled gold nanoparticle
(AuNP) delivery platform to evaluate and image the effectiveness of Gli inhibition both in vitro and in vivo.
 The first objective of this proposal is to redesign the synthetic route for coupling DNA to Co(III)-sb. The
equatorial ligand scaffold of Co(III)-sb will be functionalized with an alkyne moiety to allow for clickable
conjugation to an azide functionalized Gli consensus sequence, generating Co(III)-Gli. This is anticipated to
significantly improve yields and scalability from the current conjugation method. The second and third
objectives focus on evaluating the potency of Co(III)-Gli against Gli for the inhibition of tumor growth. Co(III)-Gli
will be hybridized to a DNA capped AuNP to generate an optimized dehybridization sequence to release the
agent at physiological temperature. Co(III)-Gli AuNPs will be labeled with Gd(III) magnetic resonance imaging
(MRI) contrast agents to provide a platform for fate mapping the conjugates both in vitro and in vivo. The ability
of Co(III)-Gli to inhibit exogenous Gli will be evaluated in vitro using human embryonic kidney cells and in vivo
using a murine model that natively develops SHH subtype MB tumors. Co(III)-Gli is anticipated to inhibit Gli
with high specificity, resulting in suppressed tumor growth.
 This project fully aligns with the mission of the NIH both in its short-term and long-term implications. It
will further develop knowledge about inhibition of cerebellar Gli transcription factors in the short-term, and
generate a platform for enhancing current treatment options for SHH subtype medulloblastoma...

## Key facts

- **NIH application ID:** 10114992
- **Project number:** 5F31CA236175-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Meghan Ward
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,860
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114992

## Citation

> US National Institutes of Health, RePORTER application 10114992, Irreversible Inhibtion of Cerebellar Gli Transcription Factors by Cobalt (III) Complexes (5F31CA236175-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114992. Licensed CC0.

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