How Protein Degraders Are Unlocking Cancer's Master Switch
For decades, the MYC oncogene has represented both the ultimate prize and most frustrating challenge in cancer therapeutics. As a master regulator of cellular proliferation, MYC drives the growth of the majority of human cancers—from breast and ovarian cancers to lethal forms of leukemia, pancreatic, and gastric cancers 4 .
When MYC goes awry, cells divide uncontrollably, resisting treatments and propelling tumor growth. Yet despite its clear importance, MYC has stubbornly resisted all attempts at targeting, earning the notorious label "undruggable" 4 .
Drives progression in over 50% of all human cancers, making it one of the most common oncogenic drivers.
MYC is an "intrinsically disordered protein"—it lacks stable structure, flitting between different shapes and making it nearly impossible for traditional small-molecule drugs to grab onto and inhibit 4 . This biological slipperiness, combined with concerns that targeting MYC might cause unbearable toxicity in healthy cells, created a decades-long stalemate in MYC-targeted therapy development 4 .
Now, a revolutionary approach called targeted protein degradation is fundamentally changing this narrative. Instead of merely blocking MYC's function, scientists are developing ingenious compounds that completely eliminate the MYC protein from cancer cells. The most advanced of these, including a clinical candidate called WBC100, are showing remarkable promise in regressing even the most lethal MYC-driven tumors 5 .
Targeted protein degradation represents a paradigm shift in drug development, moving beyond simple inhibition to complete elimination of disease-causing proteins. This innovative approach cleverly hijacks the body's own protein recycling machinery—the ubiquitin-proteasome system—which normally marks damaged or unwanted proteins for destruction 1 .
The process works through an elegant molecular relay: specialized compounds recruit cellular demolition crews called E3 ubiquitin ligases to specific target proteins. These ligases attach a "kiss of death" in the form of ubiquitin chains, signaling the proteasome—the cell's garbage disposal—to digest the marked protein into harmless fragments 1 .
Researchers have developed two primary classes of protein degraders that function through slightly different mechanisms:
| Feature | Molecular Glue Degraders | PROTACs |
|---|---|---|
| Size | Compact, low molecular weight | Larger, bifunctional |
| Mechanism | Monovalent, induces novel interactions | Bivalent, brings proteins together |
| E3 Ligase Usage | Often cereblon-based | Can use various E3 ligases |
| Administration | Generally better drug properties | Can have challenges with drug-like properties |
| Known Examples | Thalidomide derivatives, WBC100 | CDK9 degraders, MYC-targeting PROTACs |
What makes degradation particularly powerful against MYC is that it addresses both the protein's enzymatic functions and its structural roles. MYC doesn't just catalyze chemical reactions—it serves as a scaffolding protein that helps assemble complex molecular machines. Conventional inhibitors might block one function while leaving others intact, but degradation removes the entire protein, dismantling all its cancer-driving activities simultaneously 2 .
While directly targeting MYC with degraders like WBC100 has shown promise, researchers from the Koehler lab at MIT recently demonstrated an equally powerful indirect approach. Their work focuses on CDK9, a protein that plays a critical role in regulating MYC expression 2 .
CDK9 coordinates signaling events that regulate transcription and is implicated in oncogenic pathways. Previous attempts to target CDK9 with conventional inhibitors revealed a frustrating paradox: prolonged inhibition triggered a compensatory feedback mechanism that actually increased MYC expression, undermining the therapeutic intent 2 .
The team created a potent and selective CDK9-targeting PROTAC molecule with rapid degradation kinetics, allowing them to observe immediate cellular responses.
They treated various cancer cell lines with either their novel CDK9 degrader or a conventional CDK9 inhibitor, comparing the effects on MYC regulation and downstream processes.
Using advanced genomic techniques, the team mapped how each approach affected the MYC-regulated network, measuring changes in gene expression across the genome.
They evaluated how each treatment impacted nucleolar homeostasis—a cellular process critical for protein synthesis that MYC directly regulates.
| Component | Role in Experiment | Significance |
|---|---|---|
| CDK9 PROTAC | Selective degrader molecule | Induces rapid CDK9 degradation |
| CDK9 Inhibitor | Conventional inhibitory control | Allows comparison of degradation vs. inhibition |
| Cancer Cell Lines | Experimental model systems | Represent MYC-driven cancers |
| Transcriptional Profiling | Genomic analysis technique | Maps changes across MYC-regulated genes |
| Nucleolar Integrity Assays | Cellular function assessment | Measures downstream effects of MYC disruption |
The findings revealed striking differences between degradation and inhibition. While both approaches initially suppressed CDK9 activity, only degradation prevented the compensatory MYC increase seen with inhibition 2 . This fundamental difference had cascading effects throughout the MYC regulatory network.
The CDK9 degrader proved significantly more effective at disrupting MYC transcriptional regulation and subsequently destabilizing nucleolar homeostasis 2 . This enhanced efficacy likely stems from the degrader's ability to abrogate both enzymatic and scaffolding functions of CDK9—something impossible with conventional inhibition 2 .
Degradation offers a more robust strategy to overcome limitations associated with CDK9 inhibition, providing a promising alternative for targeting the MYC network in cancers where CDK9 plays a central role 2 .
| Parameter | CDK9 Inhibition | CDK9 Degradation |
|---|---|---|
| MYC Expression | Compensatory increase | Sustained suppression |
| Scaffolding Functions | Largely preserved | Completely abolished |
| Nucleolar Homeostasis | Moderately affected | Potently disrupted |
| Feedback Resistance | Develops over time | Largely prevented |
| Overall Efficacy | Limited by resistance | Enhanced and sustained |
The groundbreaking advances in MYC-targeted degradation rely on specialized research tools and methodologies. Below are key components of the protein degrader development toolkit:
The recruitment machinery that marks specific proteins for degradation. Different E3 ligases are expressed in various tissues, allowing researchers to develop tissue-specific degraders. FBXO5, for instance, is highly expressed in certain tumors, potentially enabling tumor-selective degradation 1 3 .
The execution machinery of protein degradation, including ubiquitin molecules and proteasomal complexes. Researchers often use inhibitors of these systems as experimental controls to confirm degradation occurs through this pathway 5 .
Collections of potential degrader molecules with varied target-binding and E3-ligase-binding properties. These libraries enable high-throughput screening to identify promising degrader candidates 3 .
Specially engineered mice and other animal models that express human disease targets, allowing researchers to evaluate efficacy and safety of degraders in complex biological systems before human trials 1 .
Sophisticated systems that measure protein-protein interactions and molecular proximity, enabling researchers to identify and optimize molecular glue degraders that induce novel interactions between targets and E3 ligases 3 .
The clinical translation of MYC-targeted degraders is already underway. OMO-103, a mini-protein inhibitor directly targeting MYC, has successfully completed a Phase I clinical trial, demonstrating tumor penetration and disease stabilization in approximately half of evaluable patients 4 . Meanwhile, the molecular glue degrader WBC100 has progressed into Phase I clinical evaluation after showing impressive preclinical results 5 .
Looking ahead, researchers are exploring combination therapies that integrate MYC degraders with existing treatments. The complementary approaches of direct MYC degradation and indirect pathway disruption (such as CDK9 degradation) may work synergistically to overcome resistance 4 .
Despite the excitement, significant challenges remain. The functional redundancy among MYC family members (MYC, MYCN, and MYCL) means inhibition of one may trigger compensatory upregulation of others 4 . Future degraders may need to target multiple MYC family members simultaneously. Additionally, researchers are working to develop degraders that engage tissue-specific E3 ligases—such as FBXO5, which is highly overexpressed in certain tumors—to achieve higher therapeutic indexes and reduce off-target effects 3 .
The journey to target MYC therapeutically exemplifies how rethinking fundamental approaches can transform impossible challenges into tractable problems. As researchers continue to refine these revolutionary degradation technologies, we move closer to realizing the immense potential of targeting one of cancer's most central orchestrators.