Taming the Untamable
How Scientists Are Targeting the "Undruggable" MYC Protein to Revolutionize Cancer Treatment
For decades, the MYC oncoprotein has been considered "undruggable." Now, groundbreaking research is turning this narrative on its head with revolutionary approaches like targeted protein degradation.
Introduction: The Master Switch of Cancer
In the intricate landscape of human cancer, few proteins have proven as elusive and yet as critical as the MYC oncoprotein. Dubbed the "master regulator" of cancer, MYC is dysregulated in an estimated 70% of human cancers, driving uncontrolled growth across a wide spectrum of malignancies from breast and ovarian cancers to lymphomas and leukemias 1 2 .
For decades, this pivotal protein has been labeled "undruggable"—a biological ghost that scientists could identify but not capture, its disordered structure defying conventional drug development approaches 1 .
Yet today, groundbreaking research is turning this once-pessimistic narrative on its head, with revolutionary approaches like targeted protein degradation opening new frontiers in oncology. This article explores the scientific quest to tame MYC, focusing on a pivotal experiment that represents hope for millions of cancer patients worldwide.
70%
of human cancers involve MYC dysregulation
Decades
of research to target this elusive protein
Revolutionary
new approaches showing promise
Why MYC Has Been Called "Undruggable"
The Structural Challenge
MYC's reputation as an "undruggable" target stems from its fundamental biology. Unlike most proteins targeted by pharmaceuticals, MYC lacks a stable, defined structure with deep hydrophobic pockets where small-molecule drugs can readily bind 1 2 .
Instead, much of the protein exists in what scientists call an "intrinsically disordered" state—constantly shifting its shape and evading traditional drug design approaches 1 .
MYC's Pervasive Role in Cancer
MYC operates as a master regulator of numerous cancer hallmarks, including uncontrolled proliferation, metabolic reprogramming, immune evasion, and therapy resistance 1 . It functions by pairing with its binding partner MAX, and together this heterodimer attaches to specific DNA sequences (E-boxes) to control the expression of thousands of genes 2 .
In healthy cells, MYC activity is tightly controlled, but in cancer cells, it becomes hijacked—often through gene amplification, chromosomal translocations, or disrupted signaling pathways . The consequences are devastating: MYC-driven cancers tend to be exceptionally aggressive and treatment-resistant, making the need for effective therapies all the more urgent 1 .
Breaking the Barrier: New Strategies to Target MYC
The scientific community has responded to the MYC challenge with remarkable ingenuity, developing multiple innovative approaches to indirectly or directly inhibit this elusive target.
| Approach | Mechanism of Action | Representative Candidates | Development Stage |
|---|---|---|---|
| Direct Inhibition | Disrupts MYC-MAX dimerization or DNA binding | Omomyc (OMO-103), MYCi975 | Clinical trials (OMO-103) & preclinical |
| PROTAC Degraders | Recruits E3 ubiquitin ligases to tag MYC for proteasomal degradation | WBC100 | Phase I clinical trials |
| Molecular Glue Degraders | Induces novel interactions between MYC and E3 ubiquitin ligases | Compound C1 (from screening) | Preclinical research |
| Indirect Approaches | Targets upstream regulators of MYC expression | BET inhibitors (JQ1, OTX015), CDK9 inhibitors (KB-0742) | Various clinical stages |
The Direct Approach: Mini-Proteins Like Omomyc
Among the most promising direct MYC inhibitors is Omomyc, a 91-amino-acid mini-protein that specifically disrupts MYC's interaction with MAX and impedes MYC's binding to DNA 1 .
Its clinical derivative, OMO-103, has successfully completed a Phase I clinical trial, demonstrating not only a robust safety profile but also preliminary evidence of clinical efficacy 1 .
Remarkably, in one patient with metastatic pancreatic cancer, treatment resulted in an impressive 49% reduction in total tumor burden 1 .
The Degradation Approach: PROTACs and Molecular Glues
Targeted protein degradation represents a paradigm shift in drug discovery. Instead of merely inhibiting MYC's function, these approaches aim to eliminate the oncoprotein entirely from cancer cells.
PROTACs (Proteolysis-Targeting Chimeras) are heterobifunctional molecules that simultaneously bind to MYC and an E3 ubiquitin ligase, tagging MYC for destruction by the cell's own proteasome system 1 6 .
WBC100, an oral MYC-targeting PROTAC, has progressed to Phase I clinical evaluation after showing promising tumor growth inhibition in preclinical models 1 .
A Closer Look: The Hunt for Molecular Glue Degraders of MYC
Designing a High-Throughput Screen
In a groundbreaking study published in 2025, researchers developed an innovative cell-based screening system to identify molecular glue degraders of MYC 4 . They created a specialized MYC-NanoLuc fusion construct—essentially attaching a highly sensitive luminescent tag (NanoLuc) to the MYC protein itself. This creative engineering allowed them to rapidly monitor MYC protein levels in living cells through luminescence measurements 4 .
The team transfected this construct into cells and exposed them to a library of 108,800 diverse compounds from the ChemDiv collection. Their automated high-throughput system could quickly identify which compounds caused a decrease in MYC-NanoLuc luminescence—potentially indicating MYC degradation 4 .
Validating the Screening Platform
Before screening the complete compound library, the researchers first verified their system using known MYC-downregulating compounds (G9 and SY-1365). These positive controls were successfully identified in preliminary tests, confirming the screening approach could reliably detect MYC degradation 4 .
Identifying Novel MYC-Degrading Compounds
The massive screening effort identified 14 novel compounds that consistently reduced MYC protein levels in follow-up experiments. Through rigorous dose-response studies and western blot analysis—the gold standard for protein detection—the researchers confirmed that these compounds genuinely degraded MYC rather than merely suppressing the luminescence signal 4 .
| Research Stage | Number of Compounds | Key Outcome |
|---|---|---|
| Initial Screening | 108,800 | All compounds tested for MYC degradation |
| Cherry-pick Confirmation | 14 | Confirmed MYC-downregulating activity |
| Cellular Thermal Shift Assay | 5 | Demonstrated direct binding to MYC protein |
| Lead Compound (C1) | 1 | Selected for detailed characterization |
Characterizing the Lead Compound
Further investigation focused on the most promising candidate, compound C1. Researchers determined that C1 degraded MYC with a DC50 (half-maximal degradation concentration) of approximately 5 μM—a promising potency for an initial hit compound 4 .
Most remarkably, through co-immunoprecipitation experiments, the team discovered that C1 functioned as a true molecular glue: it caused MYC proteins to self-aggregate while simultaneously blocking MYC-MAX interactions. This dual mechanism—preventing MYC's normal function while promoting its degradation—represents a potentially powerful approach to targeting this oncoprotein 4 .
Functional Impact of MYC Degradation
The critical question remained: would degrading MYC with C1 actually impair cancer cells? The answer was resoundingly positive. The researchers found that C1 selectively killed cancer cells with high MYC expression at lower concentrations than required for cells with low MYC levels 4 . Furthermore, the compound reduced expression of multiple MYC-target genes, confirming that it functionally disrupted MYC's cancer-driving transcriptional program 4 .
The Scientist's Toolkit: Essential Reagents for MYC Research
| Reagent/Tool | Primary Function | Application in MYC Research |
|---|---|---|
| CRISPR/Cas9 Systems | Gene editing and genetic screening | Identifying regulators of MYC stability and degradation pathways 8 |
| Fluorescent Protein Tags | Visualizing and quantifying proteins | Creating MYC-GFP sensors to monitor protein abundance and localization 8 |
| Ubiquitin Proteasome System Components | Mediating targeted protein degradation | E3 ligases (VHL, CRBN), E2 enzymes for PROTAC and molecular glue approaches 6 |
| Cell-Based Reporter Systems | High-throughput compound screening | MYC-NanoLuc constructs for identifying degraders 4 |
| Proteasome Inhibitors | Blocking protein degradation | Validating ubiquitin-proteasome pathway involvement (e.g., Bortezomib) 8 |
Research Progress Visualization
Current development stages of various MYC-targeting approaches:
Direct Inhibition (Omomyc)
PROTAC Degraders
Molecular Glue Degraders
Indirect Approaches
Key Research Milestones
- MYC oncogene discovery 1980s
- "Undruggable" classification 1990s-2000s
- First PROTAC concept 2001
- Omomyc preclinical success 2010s
- Molecular glue discovery for MYC 2025
The Future of MYC-Targeted Therapies
The successful identification of molecular glue degraders for MYC represents more than just a technical achievement—it signals a fundamental shift in our approach to challenging drug targets. Whereas traditional drug discovery focused on occupied binding sites, these new strategies harness the cell's own degradation machinery to eliminate problematic proteins entirely 6 .
Combination Strategies
Researchers are increasingly exploring how MYC inhibitors can synergize with existing treatments. MYC inhibition has been shown to enhance response to immunotherapy, potentially by reversing MYC-mediated immune evasion .
Biomarker Development
As MYC-targeted therapies advance, identifying biomarkers to select patients most likely to respond becomes crucial. Monitoring changes in MYC-target gene expression may provide early indicators of treatment effectiveness 1 .
Addressing Resistance
Cancer cells often develop resistance to targeted therapies. The field is already exploring how to overcome potential resistance mechanisms, such as functional redundancy among MYC family members 1 .
From Undruggable to Vulnerable
The story of MYC targeting exemplifies how scientific perseverance and innovation can transform what appears impossible into a tangible clinical opportunity. Where conventional approaches failed for decades, unconventional strategies like molecular glues and PROTACs are now demonstrating measurable progress.
The high-throughput screening experiment that identified compound C1 represents more than just a technical advancement—it embodies a new paradigm for drug discovery. By creatively combining chemical biology, high-throughput automation, and insightful mechanistic studies, researchers are developing the tools to target proteins once considered beyond reach.
While challenges remain in optimizing these compounds for clinical use and understanding potential resistance mechanisms, the progress in targeting MYC offers hope not only for cancer therapy but for approaching other "undruggable" targets across various diseases. As this research continues to advance, we move closer to a future where master regulators of cancer like MYC can be precisely controlled, potentially transforming how we treat many of the most aggressive and treatment-resistant cancers.