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 and . In this work, we performed lead optimization on MEISi-1 by synthesizing 45 novel analogues. Structure-activity relationship studies revealed the significance of a -methoxy group on ring and a hydrophobic moiety at the position of ring . 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 , α, and . Among those, , , and 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.