# Chemical Biology of IRP1-HIF2a Signaling

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $604,862

## Abstract

ABSTRACT
HIF2a is a transcription factor induced by hypoxia and tumor associated mutations. HIF2a is a
nodal regulator of cancer angiogenesis and cancer metabolism, stem cell development and
inflammation and it is validated as a therapeutic target in von Hippel-Lindau (VHL)-deficient
clear cell renal cell carcinoma (ccRCC). HIF2a had also been implicated in other diseases,
beyond ccRCC, such as glioblastoma and prostate cancer.
We identified specific HIF2a inhibitors and, by using them as chemical biology tools, we
discovered that these small molecules activate Iron Regulatory Protein 1 (IRP1) to suppress
HIF2a translation.
In this application we propose to validate IRP1 as a target for HIF2a inhibition in xenograft and
transgenic animal models of ccRCC and VHL disease. In addition, we propose to gain further
insights into the complexity of IRP1-HIF signaling by identifying the direct protein target of HIF2a
inhibitors. Finally, we propose to synthesize a series of derivatives of HIF2a inhibitors to further
improve their potency and physicochemical properties in order to generate compounds suitable
for in vivo preclinical studies and/or tools for further in vivo dissection of HIF2a biology.

## Key facts

- **NIH application ID:** 10213663
- **Project number:** 5R01CA215431-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Othon Iliopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $604,862
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213663

## Citation

> US National Institutes of Health, RePORTER application 10213663, Chemical Biology of IRP1-HIF2a Signaling (5R01CA215431-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213663. Licensed CC0.

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