Targeting the Untouchable
How Protein Degraders Are Taking Aim at Cancer's "Undruggable" MYC
For decades, cancer researchers have faced a formidable foe in the MYC protein. New strategies are finally turning the tide.
Introduction: The Master Switch of Cancer
Imagine a protein so powerful that it controls thousands of genes involved in cell growth and division, and so elusive that for decades, drug developers considered it "undruggable." This is the MYC oncoprotein—a master regulatory transcription factor that functions as a master switch for numerous human cancers 1 5 .
Cancers Driven by MYC
- Aggressive lymphomas
- Treatment-resistant breast cancer
- Ovarian cancer
- Pancreatic cancer
- And many others 5
When MYC is dysregulated, which occurs in approximately 70% of human cancers, it drives uncontrolled tumor growth and progression 1 . From aggressive lymphomas to treatment-resistant breast, ovarian, and pancreatic cancers, MYC's fingerprint is found everywhere in oncology 5 . Despite its obvious importance, MYC has stubbornly resisted all attempts at conventional drug targeting—until now. The emergence of protein degrader technology is rewriting the rules of drug design and challenging long-held assumptions about what makes a protein "undruggable."
Why MYC Has Been Deemed "Undruggable"
The challenges in targeting MYC are rooted in its unique structural characteristics, which defy traditional drug development approaches.
Nuclear Localization
MYC performs its functions inside the cell nucleus, where it regulates gene expression. This location creates additional barriers for therapeutic compounds to reach their target 1 .
High-Affinity Protein Interactions
MYC exerts its effects by forming a heterodimer (a two-protein complex) with its partner MAX. This MYC-MAX complex binds to DNA with remarkably high affinity, making it challenging to disrupt with conventional drugs 1 .
For years, these characteristics placed MYC firmly in the "undruggable" category, alongside other challenging proteins like the KRAS oncogene . However, the scientific community has recently begun rethinking this classification, driven by groundbreaking advances in biotechnology 5 .
The Protein Degrader Revolution: A New Way to Target Proteins
The limitations of traditional inhibitors have sparked interest in a revolutionary approach: Targeted Protein Degradation (TPD). Instead of merely blocking a protein's activity, TPD aims to completely remove the problematic protein from the cell.
The Proteasome: Cellular Recycling Center
At the heart of this strategy lies the ubiquitin-proteasome system—the cell's natural machinery for disposing of damaged or unwanted proteins. This system works through a sophisticated tagging process:
Ubiquitin Activation
A small protein called ubiquitin is activated by an E1 enzyme in an ATP-dependent process.
Ubiquitin Conjugation
The activated ubiquitin is transferred to an E2 conjugating enzyme.
Ubiquitin Ligation
An E3 ubiquitin ligase identifies the specific target protein and facilitates the transfer of ubiquitin from E2 to the target.
Polyubiquitination
The process repeats, building a chain of ubiquitins on the target protein.
Degradation
The proteasome recognizes the ubiquitin tag and degrades the target protein into small peptides 4 .
PROTACs: Bringing the Enemy to the Executioner
PROteolysis TArgeting Chimeras (PROTACs) are bifunctional molecules that hijack this natural degradation system. They consist of three key components:
- A warhead that binds to the target protein (MYC)
- A ligand that recruits an E3 ubiquitin ligase
- A linker connecting these two elements 4
PROTACs act as "matchmakers," bringing the target protein into close proximity with the ubiquitin machinery, leading to its tagging and subsequent destruction. The most remarkable feature of PROTACs is their catalytic nature—a single PROTAC molecule can theoretically facilitate the degradation of multiple copies of the target protein, offering significant advantages in potency over traditional inhibitors 4 .
Molecular Glues: Simpler but Smarter
An alternative degradation strategy employs molecular glues—smaller, single molecules that induce or stabilize interactions between an E3 ligase and a target protein that wouldn't normally interact. Unlike the larger, bifunctional PROTACs, molecular glues are more compact and often have better drug-like properties, though they can be more challenging to design rationally 4 .
Case Study: The MTP3 PROTAC and Its Unexpected Discovery
A recent groundbreaking study published in ACS Chemical Biology illustrates both the promise and complexity of targeting MYC with protein degraders 6 . Researchers developed a PROTAC called MTP3, designed to degrade MYC, and made some unexpected discoveries that highlight the nuances of this approach.
Methodology: Step-by-Step Experiment
PROTAC Design
The research team created MTP3 by modifying a known MYC-binding compound called KJ-Pyr-9. They attached a ligand designed to recruit an E3 ubiquitin ligase, creating a bifunctional degrader.
Cellular Treatment
Cancer cells driven by MYC were treated with MTP3 to assess its effects on MYC protein levels.
Outcome Analysis
Researchers monitored both the degradation of full-length MYC and the unexpected emergence of a truncated form using specialized laboratory techniques.
Results and Analysis: Bimodal Degradation Revealed
The experiment yielded surprising results that provided new insights into MYC regulation:
| Parameter Investigated | Observation | Scientific Significance |
|---|---|---|
| Full-length MYC degradation | Successful depletion of endogenous full-length MYC protein | Confirms PROTAC technology can target MYC for degradation |
| Emergence of tMYC | Appearance of a shorter, N-terminally truncated MYC species (tMYC) | Reveals alternative degradation outcomes beyond simple protein removal |
| tMYC functionality | tMYC retains ability to regulate genes and maintain oncogenic state | Highlights potential resistance mechanism to PROTAC treatment |
| Cellular proliferation | Cells continue to proliferate despite reduced full-length MYC | Suggests tMYC is functionally sufficient to drive cancer growth |
The most striking finding was that MTP3 treatment resulted in what the researchers termed "bimodal degradation"—while full-length MYC was successfully depleted, a truncated MYC species (tMYC) emerged. This tMYC lacks approximately 10 kDa of MYC's N-terminal transactivation domain but remains functionally capable of driving oncogenic proliferation 6 .
This discovery underscores the complexity of targeting highly dynamic proteins like MYC and demonstrates that PROTACs can induce outcomes beyond simple target degradation. It also highlights the need for careful optimization of degrader molecules to ensure complete and effective target elimination.
The Scientist's Toolkit: Essential Reagents for MYC Degradation Research
Developing protein degraders for MYC requires specialized research tools. The following table outlines key reagents and their applications in this cutting-edge field.
| Research Reagent | Function/Description | Application in MYC Research |
|---|---|---|
| PROTAC Molecules (e.g., MTP3, WBC100) | Bifunctional degraders linking MYC binders to E3 ligase ligands | Induce MYC ubiquitination and degradation; study degradation consequences 6 5 |
| Molecular Glue Degraders (e.g., MYC degrader 1) | Monovalent compounds inducing novel E3-MYC interactions | Alternative degradation strategy; often improved cellular permeability 2 4 |
| MYC Inhibitors (e.g., KJ-Pyr-9, Mycro 3) | Compounds that bind MYC and disrupt MYC-MAX dimerization | Serve as warheads for PROTAC development; study MYC functional inhibition 2 6 |
| E3 Ligase Ligands | Small molecules recruiting specific E3 ligases (e.g., VHL, CRBN) | Constitute one half of PROTAC molecules; crucial for ubiquitination 4 |
| siRNA against MYC | Small interfering RNA triggering MYC mRNA degradation | Control experiment to compare transcriptional vs. post-translational MYC inhibition 2 |
Research Progress in MYC Targeting
From Lab to Clinic: The Future of MYC-Targeted Therapies
The progress in MYC degradation is rapidly moving from theoretical concept to clinical reality. Several promising candidates have entered human trials, marking a pivotal moment in oncology drug development.
| Therapeutic Candidate | Mechanism of Action | Development Stage | Key Findings |
|---|---|---|---|
| OMO-103 | Mini-protein inhibiting MYC-MAX dimerization | Phase I Clinical Trial (NCT04808362) | Disease stabilization in ~50% of evaluable patients; 49% tumor reduction in one pancreatic cancer patient 5 |
| WBC100 | Oral PROTAC degrader of MYC | Phase I Clinical Evaluation (NCT05100251) | Preclinical studies show reduced MYC levels in tumor models with inhibited growth and extended survival 5 |
| BET Inhibitors (e.g., OTX015) | Indirect MYC targeting by blocking transcription | Phase I/II Trials (NCT01713582) | Modest efficacy in blood cancers with toxicity challenges; demonstrates indirect approach limitations 5 |
The clinical advancement of these direct MYC-targeting therapies represents a dramatic shift in oncology. As noted in a 2024 review, these innovations provide "compelling evidence for direct MYC targeting as an emerging cornerstone in precision oncology" 5 .
Current Clinical Pipeline
Development Timeline
2010-2015
Early MYC inhibitor discovery; proof-of-concept studies
2016-2020
PROTAC technology applied to MYC; first successful degraders
2021-2023
Optimization of degraders; preclinical validation
2024-Present
First clinical trials of direct MYC-targeting therapies
Conclusion: A New Era of Cancer Therapeutics
The development of protein degraders to target MYC represents more than just another incremental advance in cancer therapy—it signifies a fundamental shift in drug discovery. By moving beyond the limitations of traditional inhibitors and harnessing the cell's own degradation machinery, scientists are finally cracking one of the toughest problems in oncology.
While challenges remain—including potential resistance mechanisms like the emergence of truncated MYC variants—the progress to date has been remarkable. The once "undruggable" MYC protein is now firmly in the crosshairs of innovative therapeutic modalities, offering new hope for patients with MYC-driven cancers.
As research continues to refine these approaches and overcome existing limitations, protein degraders may well unlock a new era of cancer treatment where no oncoprotein remains untouchable. The story of MYC targeting serves as a powerful reminder that in science, "undruggable" is often just a temporary label, waiting for the right technology to come along and rewrite the rules.