Discovery of novel pyrrolo[2,3-d]pyrimidines as potent menin-mixed lineage leukemia interaction inhibitors.

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.

• Authors: Huanrong Bai, Zhe Yang, Hao Lei, Yujie Wu, Jiaxin Liu, Bo Yuan, Mengyan Ma, Li Gao, San-Qi Zhang, Minhang Xin
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 268 Pg. 116226 (Mar 15 2024) ISSN: 1768-3254 [Electronic] France
• PMID: 38367493 (Publication Type: Journal Article)
• Copyright: Copyright © 2024 Elsevier Masson SAS. All rights reserved.

Chemical References

• Myeloid-Lymphoid Leukemia Protein
• Pyrimidines

Topics

• Humans
• Myeloid-Lymphoid Leukemia Protein (metabolism)
• Leukemia (drug therapy)
• Pyrimidines (pharmacology)