Language
English
Publication Date
9-25-2025
Journal
Journal of Medicinal Chemistry
DOI
10.1021/acs.jmedchem.5c01587
PMID
40957087
PMCID
PMC12641569
PubMedCentral® Posted Date
11-25-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Mixed lineage leukemia (MLL) gene rearrangements cause ~75% of acute leukemia in infants and 5-10% in children and adults with poor clinical outcomes. Protein-protein interactions (PPI) between frequent MLL fusion partners AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Sixty-seven quinoxiline compounds were synthesized and tested for their ability to inhibit such PPIs. Compounds 16, 17, 59 and 63 were found to be potent inhibitors with IC50 values of 0.35-1.5 μM. Structure-activity relationships are discussed. Potent inhibitors can suppress expression of MLL target genes Myc and Meis1 and selectively block proliferation of MLL-r and several other leukemia cells with EC50 values as low as 0.84 μM. Compound 17 exhibited significant antitumor activities in a mouse model of MLL-r leukemia without overt toxicities. It also showed favorable pharmacokinetics in mice. These results indicate compound 17 is a promising pharmaceutical lead for treatment of MLL-r leukemia.
Keywords
Structure-Activity Relationship, Humans, Animals, Antineoplastic Agents, Methyltransferases, Mice, Cell Line, Tumor, Histone-Lysine N-Methyltransferase, Cell Proliferation, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Transcriptional Elongation Factors, Mixed lineage leukemia, Gene rearrangement, Protein-protein interaction, Small molecule inhibitors, Antitumor drug discovery, Pharmacokinetics
Published Open-Access
yes
Recommended Citation
Mishra, Chandra Bhushan; Li, Xin; Moku, Bala Krishna; et al., "Synthesis, Structure-Activity Relationships, and Antitumor Activities of Quinoxiline-Containing Inhibitors of the Protein-Protein Interactions between Transcription Coactivator AF9/ENL and DOT1L/AF4" (2025). Faculty, Staff and Students Publications. 6476.
https://digitalcommons.library.tmc.edu/baylor_docs/6476
Graphical Abstract