title: Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors.
abstract: Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Synthesis and evaluation of a previously described class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) is further described herein. Our investigation of structure-activity relationships led to the identification of potent inhibitors 14c, 14h and 16e. Key challenges included modulation of physicochemical properties and pharmacokinetic (PK) parameters to enable compound testing in a Chk1 specific hollow fiber pharmacodynamic model. In this model, 16e was shown to abrogate topotecan-induced cell cycle arrest in a dose dependent manner. The demonstrated activity of TZs in this model in combination with a chemotherapeutic agent as well as radiotherapy validates this series of Chk1 inhibitors. X-ray crystal structures (PDB code: 2YEX and 2YER) for an initial lead and an optimized analog are also presented.
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Vibha.Oza@astrazeneca.com
authors.forename: Vibha
authors.initials: V
authors.lastname: Oza
authors.forename: Susan
authors.initials: S
authors.lastname: Ashwell
authors.forename: Patrick
authors.initials: P
authors.lastname: Brassil
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.forename: Jaychandran
authors.initials: J
authors.lastname: Ezhuthachan
authors.forename: Chun
authors.initials: C
authors.lastname: Deng
authors.forename: Michael
authors.initials: M
authors.lastname: Grondine
authors.forename: Candice
authors.initials: C
authors.lastname: Horn
authors.forename: DongFang
authors.initials: D
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Lyne
authors.forename: Nicholas
authors.initials: N
authors.lastname: Newcombe
authors.forename: Martin
authors.initials: M
authors.lastname: Pass
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.forename: Dorin
authors.initials: D
authors.lastname: Toader
authors.forename: Dingwei
authors.initials: D
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Sonya
authors.initials: S
authors.lastname: Zabludoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000201:enzymology / Q000628:therapy*; D003131:Combined Modality Therapy; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D019772:Topotecan / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D019772:Topotecan; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse