UNC1062, a new and potent Mer inhibitor

•Discovery of pyazolopyrimidine sulfonamides as potent and selective Mer inhibitors.•UNC1062 selectively inhibits Mer both in purified enzymes and intact cell systems.•UNC1062 inhibits the colony formation of multiple tumor cell lines in soft agar.•The anti-tumor activity of UNC1062 further validates Mer as a therapeutic target.

Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure–activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide