# Elucidation of a structural rationale for the binding of Myc by small molecule inhibitors

> **NIH NIH F30** · NORTHWESTERN UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
Myc is a transcription factor essential for vital cellular processes such as proliferation, differentiation, metabolism
and biosynthesis. As a result, it is often coopted during malignant transformation of cells and deregulated Myc
expression occurs in virtually all cancer types. Given this role as a prominent oncogene, Myc is widely regarded
as a high value cancer target. However, direct inhibition of Myc has been unsuccessful despite decades of
research and development efforts. Myc is an intrinsically disordered protein (IDP) and therefore it lacks a unique,
defined three-dimensional structure, which has made it extremely difficult to identify small molecule inhibitors
based on traditional structure-based drug design paradigms. Instead, the protein has conformational flexibility
and can access a large variety of different structures, which explains how it can recognize and bind a diverse
assortment of protein partners dependent on cellular context. Notwithstanding the lack of any defined pockets in
the Myc protein, several groups have identified small molecules that can disrupt Myc function. However, none of
these inhibitors have made it to rigorous preclinical studies due to poor pharmacokinetic profiles and weak
potency. Furthermore, there have been little to no studies demonstrating target engagement by small molecule
probes of Myc in cells. This work is addressing these key barriers to progress.
Small molecule binding to intrinsically disordered proteins is governed by different biophysical driving forces
compared to binding of small molecules to globular, folded proteins. Binding to IDPs causes a shift in the
population of available conformations and the resulting increase in entropy is the main driver of the free energy
of binding. However, binding events only occur within regions on IDPs which are less disordered and more
hydrophobic, providing for key, despite being relatively weak, enthalpic interactions that ensure specificity of
binding. I hypothesize that Myc possesses a sequence of amino acids that serves as a small molecule
binding hotspot. Using a panel of Myc mutant constructs, coupled with biotinylated small molecule Myc binders,
I will elucidate the role of this Myc binding hotspot in small molecule recognition. I also hypothesize that a shift
in conformational space occurs as a result of binding this Myc hotspot which directly results in an
increased rate of Myc protein degradation. My preliminary data suggests that small molecule binding of Myc
promotes increased interaction with proteins involved in the Myc phosphorylation and degradation pathway.
Therefore, I will also elucidate how binding impacts Myc protein degradation. These experiments will advance
our understanding of the factors that promote binding to IDPs and how we can leverage them to progress towards
the ultimate goal of identifying a suitable clinical small molecule Myc inhibitor.

## Key facts

- **NIH application ID:** 9991098
- **Project number:** 1F30CA250196-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mihai Ioan Truica
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991098

## Citation

> US National Institutes of Health, RePORTER application 9991098, Elucidation of a structural rationale for the binding of Myc by small molecule inhibitors (1F30CA250196-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991098. Licensed CC0.

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