Lead Optimization and Structure–Activity Relationship Studies on Myeloid Ecotropic Viral Integration Site 1 Inhibitor

The
pivotal role of the myeloid ecotropic viral integration site
1 (MEIS1) transcriptional factor was reported in cardiac regeneration
and hematopoietic stem-cell (HSC) regulation with our previous findings.
MEIS1 as a promising target in the context of pharmacological
inhibition, we identified a potent myeloid ecotropic viral integration
site (MEIS) inhibitor, MEISi-1, to induce murine and human HSC expansion ex vivo and in vivo. In this work, we performed
lead optimization on MEISi-1 by synthesizing 45 novel analogues. Structure–activity
relationship studies revealed the significance of a para-methoxy group on ring A and a hydrophobic moiety at
the meta position of ring B. Obtained
biological data were supported by inhibitor docking and molecular
dynamics simulation studies. Eleven compounds were depicted as potent
inhibitors demonstrating a better inhibitory profile on MEIS1 and
target genes Meis1, Hif-1α,
and p21. Among those, 4h, 4f, and 4b were the most potent inhibitors. The predicted
pharmacokinetics properties fulfill drug-likeness criteria. In addition,
compounds exerted neither cytotoxicity on human dermal fibroblasts
nor mutagenicity.