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

> **NIH NIH U54** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $220,000

## 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. 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:** 11012072
- **Project number:** 2U54CA137788-16
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** DEREK S TAN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $220,000
- **Award type:** 2
- **Project period:** 2008-09-26 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11012072

## Citation

> US National Institutes of Health, RePORTER application 11012072, Full Project 1: Structural, chemical, and cellular probing of a new anticancer target: HIF-coactivator complexes (2U54CA137788-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11012072. Licensed CC0.

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