title: Identification of a checkpoint modulator with synthetic lethality to p53 mutants.
abstract: The G(2) checkpoint is an indispensable pathway for cancers lacking p53 function, for delaying cell cycle progression, and for completing DNA repair. Therefore, disruption of this pathway is expected to offer selective therapy for these highly prevalent cancers. The aim of this study was to identify an inhibitor of the G(2) checkpoint including the ataxia-telangiectasia-mutated and Rad3-related checkpoint kinase 1 pathway that selectively suppresses the growth of p53-deficient cells. To obtain molecules with a novel mechanism of action, we constructed a high-throughput screening system that detected abrogation of the G(2) checkpoint in X-irradiated HT-29 cells. The screening resulted in identification of a guanidine analog, CBP-93872 that dose dependently inhibited the G(2) checkpoint induced by DNA damage. Interestingly, CBP-93872 directly suppressed the growth of p53-mutated cancer cell lines with wild-type CDKN2A by eliciting G(1) arrest, but not CDKN2A-deleted and/or wild-type p53 lines. CBP-93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1, but did not suppress phospho-Chk2 or the kinase activities of either Chk1 or Chk2 in cellular or cell-free assays. These results suggest that a checkpoint modulator through suppression of Chk1 phosphorylation provides synthetic lethality to p53-deficient cells.
authors.affiliation: Pharmaceutical Research Department II, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan. haradanok@chugai-pharm.co.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sakumoto
authors.forename: Fusao
authors.initials: F
authors.lastname: Makishima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D002166:Camptothecin / Q000494:pharmacology; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D019926:Cyclin B / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects*; D019073:HT29 Cells / Q000187:drug effects / Q000528:radiation effects; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D015203:Reproducibility of Results; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000591842:CBP-93872; D019926:Cyclin B; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011412:Propanolamines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D002166:Camptothecin