# Therapeutic Inhibition of MYC:TRRAP Interaction in Cancer

> **NIH NIH R42** · COSMYC INC · 2024 · $391,403

## Abstract

PROJECT SUMMARY
The long-term product goal of this project is a small molecule cancer therapeutic targeting the MYC oncoprotein,
which is a transcriptional factor that regulates key transcriptional programs required for cellular growth and
proliferation. Due to its aberrant expression in more than 70% of human cancers and the functional validation
that MYC inhibition arrests cancer growth, MYC has been the most sought-after therapeutic target in cancer.
Despite decades of effort, therapeutic targeting of MYC has been unattainable due to a combination of factors,
including a lack of enzymatic activity or obvious ligand binding sites that can aid in inhibitor identification. Recent
research by the PI, Dr. Feris, in the Cole laboratory at Dartmouth, has uncovered an Achilles’ heel in MYC that
has enabled therapeutic targeting of this previously undruggable target. While unraveling the molecular
mechanism underlying MYC’s interaction with the TRansactivation/tRansformation-domain Associated Protein
(TRRAP), which is essential for many of the MYC-driven aberrant transcriptional programs that promote cancer,
Dr. Feris’ research revealed a vulnerability in MYC. This insight led to the development of a revolutionary
screening platform which was later deployed to screen more than 0.5 million compounds. Partial assessment of
the high-throughput screening (HTS) efforts identified several hits that not only blocked intracellular MYC:TRRAP
protein-protein interaction (PPI) at low µM potency but also potently (2 µM) attenuated 2D and 3D growth of
multiple cancer cell lines in a highly MYC-dependent manner, highlighting the specificity and selectivity of the
hits. The goal of the current Fast-Track application is hit-to-lead development of these and any additional new
hits for future clinical development as novel MYC-targeted therapeutics for cancer. The focus of the one-year
Phase I STTR portion of the Fast-Track project is to conclude hit discovery efforts by completing HTS hit
assessment while simultaneously testing the hypothesis, using our recently-identified heterocyclic amide
compound (A1), that MYC:TRRAP PPI inhibition attenuates tumor growth in a human lymphoma xenograft
model. The focus of the two-year Phase II SBIR portion of the Fast-Track project is hit-to-lead generation of
advanced leads using an iterative process combining medicinal chemistry, in vitro MYC-specific bioassays, in
vitro ADME/ tox, PK and efficacy in the mouse human lymphoma model. Identification of at least one safe and
efficacious advanced lead compound that reduces tumor burden by >50% would constitute study success. Given
the ubiquity of MYC-driven cancers, a MYC-targeted therapy, which is currently lacking, would be of immense
therapeutic value to cancer patients. This Fast-Track application will enable completion of foundational studies,
which are currently undertaken by cosMYC, Inc, a biotech company co-founded by Dr. Feris to drive the product
towards commercialization. Mor...

## Key facts

- **NIH application ID:** 10911648
- **Project number:** 1R42CA290915-01
- **Recipient organization:** COSMYC INC
- **Principal Investigator:** Ed Feris
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,403
- **Award type:** 1
- **Project period:** 2024-06-18 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911648

## Citation

> US National Institutes of Health, RePORTER application 10911648, Therapeutic Inhibition of MYC:TRRAP Interaction in Cancer (1R42CA290915-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10911648. Licensed CC0.

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