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Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
Published on: May 10, 2022
Exploiting the ubiquitin system in myeloid malignancies. From basic research to drug discovery in MDS and AML
Rares Drula1, Sabina Iluta2, Diana Gulei1
1Research Center for Advanced Medicine - MedFUTURE, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
Abstract:
The ubiquitin-proteasome system is the crucial homeostatic mechanism responsible for the degradation and turnover of proteins. As such, alterations at this level are often associated with oncogenic processes, either through accumulation of undegraded pathway effectors or, conversely, excessive degradation of tumor-suppressing factors. Therefore, investigation of the ubiquitin- proteasome system has gained much attraction in recent years, especially in the context of hematological malignancies, giving rise to efficient therapeutics such as bortezomib for multiple myeloma. Current investigations are now focused on manipulating protein degradation via fine-tuning of the ubiquitination process through inhibition of deubiquitinating enzymes or development of PROTAC systems for stimulation of ubiquitination and protein degradation. On the other hand, the efficiency of Thalidomide derivates in myelodysplastic syndromes (MDS), such as Lenalidomide, acted as the starting point for the development of targeted leukemia-associated protein degradation molecules. These novel molecules display high efficiency in overcoming the limitations of current therapeutic regimens, such as refractory diseases. Therefore, in this manuscript we will address the therapeutic opportunities and strategies based on the ubiquitin-proteasome system, ranging from the modulation of deubiquitinating enzymes and, conversely, describing the potential of modern targeted protein degrading molecules and their progress into clinical implementation.
Insights
Targeting the ubiquitin-proteasome system offers new cancer therapies. Strategies include inhibiting deubiquitinating enzymes or using targeted protein degraders for hematological malignancies.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- The ubiquitin-proteasome system (UPS) regulates protein homeostasis, and its dysregulation is linked to cancer development.
- Altered UPS function can lead to oncogene accumulation or tumor suppressor loss, driving malignant processes.
- Hematological malignancies have seen success with UPS-targeting drugs like bortezomib.
Purpose of the Study:
- To review therapeutic strategies targeting the ubiquitin-proteasome system for hematological malignancies.
- To explore the potential of modulating deubiquitinating enzymes and developing targeted protein degraders.
- To discuss the clinical progress of novel UPS-based therapeutic approaches.
Main Methods:
- Review of current literature on ubiquitin-proteasome system research in oncology.
- Analysis of therapeutic strategies involving deubiquitinating enzyme inhibitors.
- Examination of proteolysis-targeting chimera (PROTAC) systems and thalidomide derivatives.
- Assessment of clinical trial data for novel protein degradation molecules.
Main Results:
- The UPS is a validated target in hematological cancers, with existing therapies like bortezomib.
- Inhibiting deubiquitinating enzymes and developing PROTACs are promising avenues for modulating ubiquitination.
- Thalidomide derivatives have spurred the development of targeted protein degraders for leukemia.
- Novel targeted protein degraders show potential in overcoming resistance to current treatments.
Conclusions:
- The ubiquitin-proteasome system presents significant therapeutic opportunities in hematological malignancies.
- Targeted protein degradation represents a rapidly advancing field with potential for refractory diseases.
- Further clinical investigation of UPS-modulating agents and targeted degraders is warranted.
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