title: 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.
abstract: 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.
authors.affiliation: Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. p.g.wyatt@dundee.ac.uk
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Woodhead
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: Deborah J
authors.initials: DJ
authors.lastname: Davis
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Devine
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Early
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Feltell
authors.forename: E Jonathan
authors.initials: EJ
authors.lastname: Lewis
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: Matthias
authors.initials: M
authors.lastname: Reule
authors.forename: Gordon
authors.initials: G
authors.lastname: Saxty
authors.forename: Lisa C A
authors.initials: LC
authors.lastname: Seavers
authors.forename: Donna-Michelle
authors.initials: DM
authors.lastname: Smith
authors.forename: Matt S
authors.initials: MS
authors.lastname: Squires
authors.forename: Gary
authors.initials: G
authors.lastname: Trewartha
authors.forename: Margaret T
authors.initials: MT
authors.lastname: Walker
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
mesh_terms: 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
chemical_list: 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