Exploiting the ubiquitin system in myeloid malignancies. From basic research to drug discovery in MDS and AML.
Blood Rev
; 56: 100971, 2022 11.
Article
en En
| MEDLINE
| ID: mdl-35595613
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Síndromes Mielodisplásicos
/
Leucemia Mieloide Aguda
/
Mieloma Múltiple
/
Trastornos Mieloproliferativos
Límite:
Humans
Idioma:
En
Revista:
Blood Rev
Asunto de la revista:
HEMATOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Rumanía