# Chemical Probes as Allosteric Modulators of CK2 Alpha Prime Targeting Huntington's Disease

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2022 · $189,353

## Abstract

PROJECT SUMMARY
CK2α’, one of two catalytic subunits of human protein kinase CK2 holoenzyme, is inappropriately upregulated in
cellular and animal models of Huntington’s disease (HD), and in human patients with HD. There are currently no
selective inhibitors for CK2α’ available. Our work shows that CK2α’ is involved in the hyperphosphorylation and
degradation of the stress protective Heat Shock transcription Factor 1 (HSF1). HSF1 has several protective roles
in vivo, including regulation of stress protective chaperones and synaptic proteins, and energy metabolism. HSF1
levels are increased in an HD mouse model lacking one allele of CK2α’ (zQ175 HD), leading to increased
chaperone expression and excitatory synapse density, decreased HTT aggregates and inflammation, and
improved motor behavior. Given these exciting and promising results, we are initiating a program to identify
selective allosteric inhibitors of CK2α’ that can serve as chemical probes for in vitro and in vivo target validation
studies. The single specific aim of this exploratory project is to identify and characterize allosteric inhibitors of
CK2α’ that can serve as leads for selective probe development. Herein, we propose to employ an ADP-GloTM
luminescence high-throughput screen of the ChemDiv Allosteric Kinase Inhibitor (CDAKI) Library, increasing the
likelihood that we will discover a small-molecule that binds allosterically to CK2α’. Active compounds will be
further characterized by isothermal titration calorimetry (ITC) and x-ray crystallography. Confirmed active
compounds will be validated using SAR (structure-activity relationship) by commerce. Our working hypothesis is
that this library of known allosteric kinase inhibitors will generate excellent starting points for structurally-enabled
compound development leading to selective allosteric probes. The potential impact of this project on human
health is considerable. There is an unmet medical need for therapeutic agents that can halt or reverse the
cognitive and motor decline associated with HD. This work will have a positive impact on the field as it will provide
a path toward chemical probes for the validation of a new target for therapeutic development. The eventual
development of a selective allosteric inhibitor of CK2α’ would address this unmet medical need and represent a
significant advancement in the field of HD.

## Key facts

- **NIH application ID:** 10348753
- **Project number:** 5R21NS116260-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Rocio Gomez-Pastor
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $189,353
- **Award type:** 5
- **Project period:** 2021-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348753

## Citation

> US National Institutes of Health, RePORTER application 10348753, Chemical Probes as Allosteric Modulators of CK2 Alpha Prime Targeting Huntington's Disease (5R21NS116260-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10348753. Licensed CC0.

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