title: 1-(5-Chloro-2-alkoxyphenyl)-3-(5-cyanopyrazin-2-yl)ureas [correction of cyanopyrazi] as potent and selective inhibitors of Chk1 kinase: synthesis, preliminary SAR, and biological activities.
abstract: The discovery of 1-(5-chloro-2-alkoxyphenyl)-3-(5-cyanopyrazin-2-yl)ureas as a new class of potent (IC(50) values of 3-10 nM) and selective inhibitors of Chk1 kinase was described. One of these compounds (2e) potentiates HeLa cells by over 22-fold against doxorubicin in an antiproliferation assay, and SW620 cells against camptothecin by 20-fold in an antiproliferation assay and 14-fold in a soft agar assay. Flow cytometry (FACS) analysis confirmed that 2e abrogated G2 checkpoint arrest of H1299 cells caused by doxorubicin and S checkpoint arrest caused by camptothecin.
authors.affiliation: Cancer Research, Global Pharmaceutical R and D, Abbott Laboratories, Abbott Park, Illinois 60064, USA. gary.t.wang@abbott.com
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: Gaoquan
authors.initials: G
authors.lastname: Li
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mantei
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Wendy
authors.initials: W
authors.lastname: Gu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xiao
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowin
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D004317:Doxorubicin; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002166:Camptothecin