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

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.

Anti-proliferative activity; MLL-R leukemia; Menin-MLL interaction inhibitors; Pyrrolo[2,3-d]pyrimidine.