title: Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors.
abstract: Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA. gcuny@rics.bwh.harvard.edu
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Ulyanova
authors.forename: Debasis
authors.initials: D
authors.lastname: Patnaik
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Liu
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Lin
authors.forename: Ken
authors.initials: K
authors.lastname: Auerbach
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Ray
authors.forename: Jun
authors.initials: J
authors.lastname: Xian
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.forename: Ross L
authors.initials: RL
authors.lastname: Stein
authors.forename: Jonathan M G
authors.initials: JM
authors.lastname: Higgins
mesh_terms: D000818:Animals; D002243:Carbolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D002243:Carbolines; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C530656:HASPIN protein, human