Discovery of novel pyrrolo[2,3-d]pyrimidines as potent menin-mixed lineage leukemia interaction inhibitors.
Eur J Med Chem
; 268: 116226, 2024 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-38367493
ABSTRACT
To interfere the Menin-MLL interaction using small molecular inhibitors has been shown as new treatment of several special hematological malignancies. Herein, a series of Menin-MLL interaction inhibitors with pyrrolo[2,3-d]pyrimidine scaffold were designed, synthesized and evaluated. Among them, compound A6 exhibited potent binding affinity with an IC50 value of 0.38 µM, and strong anti-proliferative activity against MV4-11 cells with an IC50 value of 1.07 µM. Further study showed A6 reduced the transcriptional levels of HOXA9 and MEIS1 genes. Moreover, A6 induced cellular apoptosis, arrested the cell cycle in G0/G1 phase, and reversed the differentiation arrest in a concentration-dependent manner. This study suggested compound A6 was as a novel potent Menin-MLL interaction inhibitor, and it proved that introduction of 4-amino pyrrolo[2,3-d]pyrimidine to occupy the P10 hydrophobic pocket was new idea for design of novel Menin-MLL interaction inhibitors.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Leucemia
/
Proteína de la Leucemia Mieloide-Linfoide
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2024
Tipo del documento:
Article