title: The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106.
abstract: Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromised G(1)-S checkpoint control. This has led to the hypothesis that S and G(2)-M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53-deficient background, as normal cells would be rescued at the G(1)-S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage-linked S and G(2)-M checkpoint control. SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased gammaH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Surrey, United Kingdom. Mike.Walton@icr.ac.uk
authors.forename: Michael I
authors.initials: MI
authors.lastname: Walton
authors.forename: Paul D
authors.initials: PD
authors.lastname: Eve
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Alexis
authors.initials: A
authors.lastname: De Haven Brandon
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Boxall
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: David H
authors.initials: DH
authors.lastname: Williams
authors.forename: John C
authors.initials: JC
authors.lastname: Reader
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009153:Mutagens / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007546:Isoquinolines; D009153:Mutagens; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C547874:SAR 020106; D003841:Deoxycytidine; D000077146:Irinotecan; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D002166:Camptothecin; D000093542:Gemcitabine