title: Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas.
abstract: Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. vibha.oza@gmail.com
authors.forename: Vibha
authors.initials: V
authors.lastname: Oza
authors.forename: Susan
authors.initials: S
authors.lastname: Ashwell
authors.forename: Lynsie
authors.initials: L
authors.lastname: Almeida
authors.forename: Patrick
authors.initials: P
authors.lastname: Brassil
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.forename: Chun
authors.initials: C
authors.lastname: Deng
authors.forename: Thomas
authors.initials: T
authors.lastname: Gero
authors.forename: Michael
authors.initials: M
authors.lastname: Grondine
authors.forename: Candice
authors.initials: C
authors.lastname: Horn
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
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: Shannon
authors.initials: S
authors.lastname: Ready
authors.forename: Siân
authors.initials: S
authors.lastname: Rowsell
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.forename: Dorin
authors.initials: D
authors.lastname: Toader
authors.forename: Melissa
authors.initials: M
authors.lastname: Vasbinder
authors.forename: Dingwei
authors.initials: D
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
authors.forename: Sonya
authors.initials: S
authors.lastname: Zabludoff
authors.forename: James
authors.initials: J
authors.lastname: Janetka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015195:Drug Design; D004357:Drug Synergism; D057166:High-Throughput Screening Assays; D000077146:Irinotecan; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D003841:Deoxycytidine; D000077146:Irinotecan; D014508:Urea; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; D002166:Camptothecin; D000093542:Gemcitabine