A breakthrough in molecular glues offers new hope for treating MYC-driven cancers
For decades, cancer researchers have battled what many considered an "undruggable" enemy—the MYC oncoprotein. Often described as a master conductor of cancer growth, MYC drives cell proliferation, metabolism, and survival pathways gone awry. This protein is deregulated in over half of all human cancers, including aggressive blood cancers and small cell lung cancers (SCLC), where it fuels uncontrolled tumor growth and resistance to therapy 5 8 .
MYC lacks the deep pockets or "crevices" that most small-molecule drugs need to bind and inhibit their targets 1 .
Deregulated in >50% of all human cancers, making it one of the most common oncogenic drivers.
The scientific community has witnessed the emergence of a revolutionary class of therapeutics called targeted protein degraders. Unlike traditional inhibitors that merely block protein activity, these degraders actually eliminate the problematic proteins from cancer cells altogether 6 .
The molecular glue binds to a specific E3 ubiquitin ligase (cereblon)
The binding changes the ligase's shape, allowing it to recognize MYC
The ligase attaches ubiquitin molecules to mark MYC for destruction
The proteasome complex breaks down the tagged MYC protein
In 2022, researchers unveiled an exciting new molecular glue dubbed GT19630 (also known as a cereblon E3 ligase modulator or CELMoD). This compound exhibits a remarkable ability to simultaneously degrade both MYC and another protein called GSPT1 (G1 to S phase transition protein 1) 1 9 .
Simultaneously degrades both MYC and GSPT1 proteins
Creates a one-two punch against cancer cells
Effective at low nanomolar concentrations
| Cancer Type | Model System | Key Finding | Dosing Regimen |
|---|---|---|---|
| MYC-driven blood cancers | HL60 xenograft | Complete tumor regression | 3 days on/7 days off |
| Small cell lung cancer | SCLC xenograft | Complete tumor regression | 3 days on/7 days off |
| Multiple cancer types | 14 breast cancer cell lines | Low nanomolar activity across subtypes | Various concentrations |
| Tissue Type | MYC Degradation | Implication |
|---|---|---|
| Tumor tissue (HL60, SCLC) | Significant | Direct anti-cancer effect |
| Normal tissue (rat spleen) | Minimal | Reduced potential toxicity |
| Approach | Effective Concentration | Key Limitation |
|---|---|---|
| Traditional inhibitors | Micromolar (≥0.5 μM) | Lower potency |
| Molecular glues | Nanomolar 1 | Dual targets require monitoring |
| Indirect inhibition | Varies | Off-target effects |
| Reagent/Method | Function in Research | Specific Example |
|---|---|---|
| Biotin-labelled GT19630 | Allows pull-down experiments to confirm direct binding between GT19630 and MYC protein | Binding inhibited by non-biotin-labeled compound 1 |
| Xenograft models | Testing compound efficacy in living organisms with human tumor transplants | HL60 AML and SCLC models showing complete regression 9 |
| Western blot analysis | Detecting and quantifying protein levels to confirm degradation of targets | Verified MYC and GSPT1 degradation following treatment 1 |
| Cell viability assays | Measuring anti-proliferative effects across cancer cell lines | 14 breast cancer cell lines representing molecular subtypes 1 |
| Flow cytometry | Analyzing cell cycle arrest and apoptosis | Used with Annexin-V-FITC Apoptosis Detection Kit 1 |
The development of GT19630 represents more than just another potential cancer drug—it exemplifies a fundamental shift in how we approach "undruggable" targets in oncology. By successfully targeting MYC, once considered nearly impossible to drug, this research opens doors to addressing other challenging cancer drivers.
GT19630 triggers a degradation event and can then be cleared from the system, offering advantages over traditional drugs that require continuous exposure 9 .
The dual degradation of both MYC and GSPT1 requires careful monitoring in clinical trials to establish a favorable balance between efficacy and potential toxicity.
Researchers have emphasized that while these preclinical findings are promising, they "should now be confirmed in an animal model system" before progressing to human trials 1 .