How Targeting USP28 Could Revolutionize Burkitt Lymphoma Treatment
Imagine a cancer that can double in size in less than a day—a disease so aggressive it represents one of the fastest-growing human malignancies.
This is Burkitt lymphoma, a rare but devastating form of non-Hodgkin lymphoma that predominantly affects children and young adults. Named after Dr. Denis Burkitt, who first documented the disease in African children in the 1950s, this cancer has long posed a significant challenge to oncologists worldwide 9 .
In approximately 85% of cases, a chromosomal translocation places the powerful MYC oncogene under control of highly active immunoglobulin gene regulators 9 .
While intensive chemotherapy can cure up to 90% of pediatric patients with limited disease, those with advanced or relapsed Burkitt lymphoma face grim prospects 9 .
Comparative survival rates in Burkitt lymphoma patients
The MYC protein has long been considered "undruggable" by conventional pharmaceutical approaches. Unlike many proteins that medicines target, MYC lacks well-defined pockets where small molecules can bind and inhibit its function.
Enter USP28, a deubiquitinating enzyme that has emerged as a promising indirect strategy to tackle MYC-driven cancers. USP28 functions as a molecular stabilizer for MYC and other cancer-promoting proteins 1 8 .
In healthy cells, proteins are constantly being produced and broken down in a carefully balanced process. When a protein like MYC is marked for destruction, it receives a molecular "kiss of death" in the form of ubiquitin chains.
USP28 removes ubiquitin chains, rescuing MYC from degradation
Overactive USP28 ensures excess MYC remains stable
Inhibit USP28 to promote MYC destruction
The quest to develop effective USP28 inhibitors has been a story of scientific ingenuity and persistence. The challenge is particularly formidable because USP28 closely resembles another deubiquitinating enzyme, USP25, with whom it shares 57% sequence identity in their catalytic domains 5 .
Testing hundreds of thousands of synthetic molecules to identify lead compounds 2 .
Improving potency, selectivity, and drug-like properties of lead compounds 2 .
Revealing how inhibitors bind to specific pockets in USP28 5 .
One of the most promising candidates to emerge from this process is CT1113, a potent USP28 inhibitor that demonstrates significant anti-cancer activity. Researchers discovered that semi-methylation at a specific 3-amino group was critical for its inhibitory power 2 .
To understand how researchers demonstrated the potential of USP28 inhibition for treating Burkitt lymphoma, let's examine a pivotal experiment using the inhibitor CT1113, as detailed in a 2022 study published in Signal Transduction and Targeted Therapy 2 .
The research team took a comprehensive approach to validate CT1113's potential:
The experimental results provided strong evidence for CT1113's therapeutic potential:
| Cell Line | c-MYC Reduction | Time Frame |
|---|---|---|
| Ramos | Dramatic decrease | 1-2 hours |
| Daudi | Dramatic decrease | 1-2 hours |
| Raji | Dramatic decrease | 1-2 hours |
In vivo efficacy of CT1113 in Burkitt lymphoma xenograft models 2
CT1113 demonstrated significant anti-tumor activity in vivo. In mice bearing Burkitt lymphoma xenografts, CT1113 treatment resulted in substantial suppression of tumor growth compared to vehicle-treated controls, with approximately 60% reduction in tumor volume and 55% reduction in tumor weight 2 .
Advancing USP28 inhibitors from laboratory concepts to potential medicines requires a sophisticated array of research tools and methodologies.
| Tool/Technique | Function in Research | Application in USP28 Studies |
|---|---|---|
| Ubiquitin-AMC assay | High-throughput screening for DUB inhibitors | Identified initial lead compounds like CT1113 2 |
| X-ray crystallography | Determines 3D protein structure with bound inhibitors | Revealed allosteric binding pocket for inhibitors like AZ1 5 |
| Surface plasmon resonance (SPR) | Measures binding kinetics between inhibitor and target | Confirmed CT1113 binding to USP28 with similar affinity for USP25 2 |
| Co-immunoprecipitation (Co-IP) | Detects protein-protein interactions in cells | Validated disruption of USP28-53BP1 complex by inhibitors 1 |
| Cycloheximide chase assay | Measures protein degradation rates | Showed accelerated c-MYC degradation after USP28 inhibition 2 |
These tools have been instrumental in developing and validating USP28 inhibitors:
The combination of cellular assays with in vivo xenograft models has created a comprehensive framework for evaluating potential USP28-targeted therapies.
Integrated approach from molecular screening to preclinical validation
The compelling preclinical data on USP28 inhibitors like CT1113 opens exciting possibilities for Burkitt lymphoma treatment. The strategy of targeting the protein stabilization machinery rather than the oncoprotein itself represents a paradigm shift in cancer therapy that could potentially be applied to other "undruggable" targets.
While CT1113 still inhibits both USP28 and USP25, researchers are actively working to develop more selective compounds. The discovery of Otilonium Bromide as a USP28 inhibitor with moderate selectivity over USP25 suggests that different chemical scaffolds might offer improved specificity 8 .
The future of USP28-targeted therapy may also lie in combination approaches. Combining USP28 inhibitors with conventional chemotherapy or other targeted agents could potentially enhance efficacy and reduce the likelihood of resistance development 2 .
The story of USP28 inhibition serves as a powerful reminder that even "undruggable" targets like MYC may have accessible weaknesses—we just need to look at the problem from the right angle.
The journey to develop USP28 inhibitors for Burkitt lymphoma represents a fascinating convergence of basic biology, structural insights, and medicinal chemistry. From understanding the fundamental role of USP28 in stabilizing the MYC oncoprotein to designing precise molecules that disrupt this interaction, researchers have built a compelling case for targeting this previously overlooked enzyme.
While challenges remain in optimizing selectivity and understanding the full therapeutic implications, the progress so far offers genuine hope for patients with this aggressive lymphoma. As research advances, USP28 inhibitors may soon join the arsenal of targeted therapies, potentially providing a more effective and less toxic alternative to current intensive chemotherapy regimens.