# Project 1: Structural and chemical probing of a new anticancer target: HIF-coactivator complexes

> **NIH NIH U54** · CITY COLLEGE OF NEW YORK · 2024 · $196,250

## Abstract

Project summary
Eukaryotic bHLH/PAS (basic helix-loop-helix/Per-ARNT-Sim) transcription factors play a critical role in regulating
cellular responses to hypoxia, xenobiotic compounds, and several other environmental conditions. Deregulation
of these pathways is highly correlated with several forms of cancer, including solid tumor onset and progression,
as best exhibited by links between overexpression of HIF (Hypoxia Inducible Factor) isoforms and predisposition
to kidney cancers. The PAS domains within these transcription factors are attractive targets for small molecule
regulation given the role that these domains play as cofactor-regulated protein/protein interaction domains in a
wide range of sensory proteins throughout biology. Here we propose to combine the complementary strengths
of the Gardner lab (CCNY) and Tan lab (MSK) for a multi-pronged attack on studying the structure and artificial
regulation of interactions between ARNT (aryl hydrocarbon nuclear receptor translocator), a common element of
several bHLH/PAS heterodimeric complexes, and several coactivator proteins that are essential for ARNT
function. Preliminary data strongly support the feasibility of this project, including cryoEM and other biophysical
data on several ARNT complexes and moderate potency small-molecule inhibitors of ARNT/CCC interactions.
Coupled with the expertise of the two groups with the requisite assays and methods, plus their past experience
in comparable projects, there is substantial confidence in this project catalyzing interactions between the two
labs and developing novel routes for small molecule regulation of cancer-driving transcription factors using an
integrated strategy of structural, chemical, and cellular research approaches.
Relevance
We propose to combine the expertise in the Gardner and Tan labs in structural biology, biochemistry, and
synthetic organic chemistry to characterize and inhibit interactions between the ARNT transcriptional regulator
and a series of coactivator proteins. Misregulation of ARNT-containing complexes are correlated with a variety
of cancers; results from our work will both guide understanding of how such complexes are assembled and guide
development of small molecule tool compounds to control their formation.

## Key facts

- **NIH application ID:** 11011996
- **Project number:** 2U54CA132378-16
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** Kevin H Gardner
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $196,250
- **Award type:** 2
- **Project period:** 2008-09-26 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11011996

## Citation

> US National Institutes of Health, RePORTER application 11011996, Project 1: Structural and chemical probing of a new anticancer target: HIF-coactivator complexes (2U54CA132378-16). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11011996. Licensed CC0.

---

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