# Chemical Approaches to Modulate PAX3-FOXO1 in Fusion-Positive Alveolar Rhabdomyosarcoma

> **NIH NIH UM1** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $2,326,552

## Abstract

PROJECT SUMMARY/ABSTRACT
Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) remains a poorly understood but highly fatal cancer
of childhood. The pathognomonic fusion oncoprotein of ARMS is PAX3-FOXO1 (i.e., PAX3::FOXO1, P3F), a
transcription factor fusion driving ARMS progression through dysregulation of gene expression and chromatin
state. Major obstacles to the development of therapies for FP-RMS and other oncogenic fusion proteins
include the high degree of conformational plasticity of the fusion protein drivers and the lack of knowledge
about protein partners or suitable mechanisms for inhibiting or clearing the fusions. To solve these gaps, we
need a comprehensive, coordinated approach to discover and develop chemical agents that clarify the
relevance of various molecular mechanisms capable of inhibiting PAX3-FOXO1-mediated tumorigenesis. We
assembled a team of chemical biologists, medicinal chemists and RMS-focused physician-scientists whose
unique and complementary expertise in high-throughput screening, chemoproteomics, quantitative molecular
interaction analyses, transcriptional biology, medicinal chemistry, pharmacology and RMS biology will be
applied to the discovery and development of small molecules that impact PAX3-FOXO1 function in FP-RMS.
A key goal of the Center is to explore multiple mechanisms of action for targeting PAX3-FOXO1 and efforts
will emphasize 1) identifying direct small-molecule binders of PAX3-FOXO1 or nearest neighbor proteins that
may be pursued as direct functional modulators or silent binders for degrader development, 2) development
of PAX3-FOXO1 degraders, including heterobifunctional proteolysis targeting chimeras (PROTACs) and
molecular glues that degrade a target by hijacking the ubiquitin-proteasome system, and 3) indirect targeting
of PAX3-FOXO1 by targeting transcriptional network collaborators that modulate the function of the fusion or
that control transcription of the fusion. We propose three complementary Projects supported by four Research
Groups, including the High-Throughput Screening Group (HTS), the Molecular & Cellular Mechanism Group
(MCM), the Medicinal Chemistry Group (Med Chem), and the Pharmacology Group (Pharm). The Specific
Aims involve all four Research Groups and include: 1) Ligand Discovery for PAX3-FOXO1 (Project 1); 2.
Discovery and Development of Targeted Protein Degraders for PAX3-FOXO1 (Project 2); and 3. Targeting
the PAX3-FOXO1-associated core regulatory transcriptional complex (Project 3). While the aims to explore
multiple pharmacologic modes of perturbing PAX3-FOXO1 activities are ambitious, our combined expertise
and experience in balancing foraging and focusing in drug discovery or development will enable our goal of
accelerating the identification of therapies for PAX3-FOXO1-positive FP-RMS. Our unique strengths will also
inform the TFCC Network, resulting in knowledge generalizable to targeting of fusion oncoproteins in
childhood cancer and accelerating advances in clin...

## Key facts

- **NIH application ID:** 10987609
- **Project number:** 1UM1CA294108-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ALEX B BURGIN
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,326,552
- **Award type:** 1
- **Project period:** 2024-09-06 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987609

## Citation

> US National Institutes of Health, RePORTER application 10987609, Chemical Approaches to Modulate PAX3-FOXO1 in Fusion-Positive Alveolar Rhabdomyosarcoma (1UM1CA294108-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10987609. Licensed CC0.

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