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 <i>ex vivo</i> and <i>in vivo</i>. In this work, we performed lead optimization on MEISi-1 by synthesizing 45 novel analogues. Structure–activity relationship studies revealed the significance of a <i>para</i>-methoxy group on ring <b>A</b> and a hydrophobic moiety at the <i>meta</i> position of ring <b>B</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 <i>Meis1</i>, <i>Hif-1</i>α, and <i>p21</i>. Among those, <b>4h</b>, <b>4f</b>, and <b>4b</b> 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.