MEIS inhibitor development process. Targeting homeodomain of MEIS proteins and scoring against other TALE homeodomain proteins allowed to identify MEIS specific small molecules from in silico screening. We have targeted the MEIS-DNA interaction. This is followed by in vitro and in vivo validations. We have shown that small molecules named MEISi-1 and MEISi-2 inhibit MEIS-Luciferase reporters. Inhibition of MEIS proteins could functionally extend self-renewal of murine and human HSPCs ex vivo. Inhibition of MEIS proteins results in downregulation of Meis1, Meis2 and MEIS target genes including Hif-1α, Hif-2α and a number of HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of key MEIS target genes. MEIS inhibitors could be used to modulate human BM mPB HSC self-renewal as evident by increased number of CD34+CD38− cells.