A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia.
ChemMedChem
; 16(9): 1391-1402, 2021 05 06.
Article
en En
| MEDLINE
| ID: mdl-33534953
ABSTRACT
Targeting protein-protein interactions (PPIs) with small-molecule inhibitors has become a hotbed of modern drug development. In this review, we describe a new class of PPI inhibitors that block menin from binding to MLL proteins. Menin is encoded by the MEN1 tumor suppressor, but acts as an essential cofactor for MLL/KMT2A-rearranged leukemias. The most promising menin-MLL inhibitors belong to the thienopyrimidine class and have recently entered phase I/II clinical trials for treating acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations. As single agents, thienopyrimidine compounds eradicate leukemia in a xenograft models of primary leukemic cells belonging to the MLL-rearranged or NPM1-mutant subtypes. These compounds are well tolerated with few or no side effects, which is remarkable given the tumor-suppressor function of menin. The menin-MLL inhibitors highlight how leukemia patients could benefit from a targeted epigenetic therapy with novel PPI inhibitors obtained by directed chemical evolution.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania