title: Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.
abstract: Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.
authors.affiliation: Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. s.howard@astex-therapeutics.com
authors.forename: Steven
authors.initials: S
authors.lastname: Howard
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.forename: John A
authors.initials: JA
authors.lastname: Boulstridge
authors.forename: Maria G
authors.initials: MG
authors.lastname: Carr
authors.forename: David M
authors.initials: DM
authors.lastname: Cross
authors.forename: Jayne
authors.initials: J
authors.lastname: Curry
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Devine
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Early
authors.forename: Lynsey
authors.initials: L
authors.lastname: Fazal
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Gill
authors.forename: Michelle
authors.initials: M
authors.lastname: Heathcote
authors.forename: Sarita
authors.initials: S
authors.lastname: Maman
authors.forename: Julia E
authors.initials: JE
authors.lastname: Matthews
authors.forename: Rachel L
authors.initials: RL
authors.lastname: McMenamin
authors.forename: Eva F
authors.initials: EF
authors.lastname: Navarro
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Brien
authors.forename: Marc
authors.initials: M
authors.lastname: O'Reilly
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.forename: Matthias
authors.initials: M
authors.lastname: Reule
authors.forename: Dominic
authors.initials: D
authors.lastname: Tisi
authors.forename: Glyn
authors.initials: G
authors.lastname: Williams
authors.forename: Mladen
authors.initials: M
authors.lastname: Vinković
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D014508:Urea; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases