title: UNC1062, a new and potent Mer inhibitor.
abstract: 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.
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: Deborah
authors.initials: D
authors.lastname: Deryckere
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Cummings
authors.forename: Debra
authors.initials: D
authors.lastname: Hunter
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Chatura N
authors.initials: CN
authors.lastname: Jayakody
authors.forename: Nancy
authors.initials: N
authors.lastname: Cheng
authors.forename: Catherine
authors.initials: C
authors.lastname: Simpson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Norris-Drouin
authors.forename: Susan
authors.initials: S
authors.lastname: Sather
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.forename: William P
authors.initials: WP
authors.lastname: Janzen
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; C586274:UNC1062; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: Glioblastoma; KAAPXWSYROPAEL-GUAVBDGJSA-N; Leukemia; Mer inhibitors; Non-small cell lung cancer; Pyrazolopyrimidines; Sulfonamides