title: Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors.
abstract: Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4-fold selectivity over haspin was also identified.
authors.affiliation: Brigham & Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA. gcuny@rics.bwh.harvard.edu
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Maxime
authors.initials: M
authors.lastname: Robin
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Ulyanova
authors.forename: Debasis
authors.initials: D
authors.lastname: Patnaik
authors.forename: Valerie
authors.initials: V
authors.lastname: Pique
authors.forename: Gilles
authors.initials: G
authors.lastname: Casano
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Liu
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Lin
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: D000166:Acridines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D000166:Acridines; 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