UNC1062, a new and potent Mer inhibitor

• DOI: 10.1016/j.ejmech.2013.03.035
• Publication Date: 2013-04-02T15:29:01Z
• Authors: Jing Liu; Weihe Zhang; Michael A. Stashko; Deborah DeRyckere; Christopher T. Cu...; Debra Hunter; Chao Yang; Chatura N. Jayakody; Nancy Cheng; Catherine Simpson; Jacqueline Norris...; Susan Sather; Dmitri Kireev; William P. Janzen; H. Shelton Earp; Douglas K. Graham; Stephen V. Frye; Xiaodong Wang
• Keywords: hERG; Phenotypic screening; IC50

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.