Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia.

A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-d]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound A13 exhibited potent anti-proliferative activity against MV4-11 cells (0.379 ± 0.182 μM). Besides, mechanistic studies confirmed A13 disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLL-rearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, A13 exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (T = 1.67 h) and high plasma exposure (AUC = 2241 ng h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.