title: Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors.
abstract: Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. Zhi-Fu.Tao@abbott.com
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Wendy
authors.initials: W
authors.lastname: Gu
authors.forename: Mai-Ha
authors.initials: MH
authors.lastname: Bui
authors.forename: Philip
authors.initials: P
authors.lastname: Merta
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Eric
authors.initials: E
authors.lastname: Johnson
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Russell
authors.initials: R
authors.lastname: Judge
authors.forename: Saul
authors.initials: S
authors.lastname: Rosenberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowin
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D004317:Doxorubicin; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002166:Camptothecin