First-in-class, selective, drug-like small molecule MEIS inhibitors
Meis1 was first discovered in BXH-2 mouse leukemia model. Studies in the last decade have shown that Meis1 has crucial roles in cellular metabolism, redox state, and tumorigenesis. Meis1 maintains cytoplasmic glycolysis through transactivation of hypoxic tumor markers, namely Hif-1α and Hif-2α. MEIS proteins includes MEIS1, MEIS2 and MEIS3 proteins. MEIS proteins have been shown to interact with PBX and HOXA9 proteins. MEIS proteins are known as an oncogene and overexpressed in various cancers including leukemia. Intriguingly, a high level of Meis1 expression was found to be associated with resistance to conventional chemotherapies (Reviewed in Current drug targets).
We have used in silico, in vitro and in vivo approaches to identify small-molecule MEIS inhibitors (MEISi). In silico screening of a million druggable small molecules allowed us to identify putative MEISi. MEIS dependent luciferase reporter assays were used to validate in vitro efficacy of MEIS inhibitors. Small molecules named MEISi-1 and MEISi-2 demonstrated a significant inhibition of MEIS-luciferase activity. In addition, inhibition of MEIS protein resulted in downregulation of MEIS target gene expression in human and animal studies in ex vivo and in vivo, respectively.