Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
Wyatt
Paul G
PG
Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. p.g.wyatt@dundee.ac.uk
Woodhead
Andrew J
AJ
Berdini
Valerio
V
Boulstridge
John A
JA
Carr
Maria G
MG
Cross
David M
DM
Davis
Deborah J
DJ
Devine
Lindsay A
LA
Early
Theresa R
TR
Feltell
Ruth E
RE
Lewis
E Jonathan
EJ
McMenamin
Rachel L
RL
Navarro
Eva F
EF
O'Brien
Michael A
MA
O'Reilly
Marc
M
Reule
Matthias
M
Saxty
Gordon
G
Seavers
Lisa C A
LC
Smith
Donna-Michelle
DM
Squires
Matt S
MS
Trewartha
Gary
G
Walker
Margaret T
MT
Woolford
Alison J-A
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship
C531230:4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D051357:Cyclin-Dependent Kinase 2