Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.
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.
Howard
Steven
S
Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. s.howard@astex-therapeutics.com
Berdini
Valerio
V
Boulstridge
John A
JA
Carr
Maria G
MG
Cross
David M
DM
Curry
Jayne
J
Devine
Lindsay A
LA
Early
Theresa R
TR
Fazal
Lynsey
L
Gill
Adrian L
AL
Heathcote
Michelle
M
Maman
Sarita
S
Matthews
Julia E
JE
McMenamin
Rachel L
RL
Navarro
Eva F
EF
O'Brien
Michael A
MA
O'Reilly
Marc
M
Rees
David C
DC
Reule
Matthias
M
Tisi
Dominic
D
Williams
Glyn
G
Vinković
Mladen
M
Wyatt
Paul G
PG
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
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