# Identification and characterization of selective azaphilone inhibitors of HuR-mRNA interactions

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $34,845

## Abstract

PROPOSAL SUMMARY
RNA-binding proteins (RBPs) regulate gene expression through binding to mRNAs, thus influencing rates of
translation, mRNA subcellular location, and mRNA half-life. The specific functional outcome of an RBP-mRNA
interaction is dependent on the identity of both binding partners. However, it is challenging to predict the
functional consequences of a specific interaction due to the diverse combinations of RBP-mRNA interactions
that occur within the cell. The RBP HuR binds has a multitude of different mRNA binding partners, allowing HuR
to control many critical cellular functions. Dysregulation of the HuR-mRNA interaction network is notably
implicated in cancers such as colon, lung, and pancreatic cancers, the three most deadly cancers in the United
States. A recently discovered azaphilone HuR inhibitor is very potent but lacks the selectivity required for
therapeutic development or to dissect the complex network of HuR mRNA binding partners. Traditional synthetic
methods are a major roadblock towards enantioselective azaphilone synthesis, making it infeasible to screen
analogs for more favorable bioactivity. However, recent innovation has produced a straightforward, one-pot
biocatalytic route that can be used to generate large, diverse azaphilone libraries. I aim to identify novel
azaphilones that act as potent and selective HuR-mRNA inhibitors using a combined biocatalytic generation and
HuR binding assay platform. I will characterize and validate HuR-azaphilone interactions and identify selective
azaphilone inhibitors of HuR both in vitro and in cellulo. Next, I will investigate functional implications of disrupting
specific HuR-mRNA interactions in a cancer cell model. Completion of the proposed work will result in the
identification and characterization of novel azaphilones that are potent and selective HuR-mRNA interactions
and can be further developed as chemical probes and cancer therapeutics.

## Key facts

- **NIH application ID:** 10536274
- **Project number:** 1F31CA275088-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Tessa Epstein
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,845
- **Award type:** 1
- **Project period:** 2022-08-06 → 2024-08-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536274

## Citation

> US National Institutes of Health, RePORTER application 10536274, Identification and characterization of selective azaphilone inhibitors of HuR-mRNA interactions (1F31CA275088-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536274. Licensed CC0.

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