title: Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.
abstract: Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Stokes
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Browne
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Foloppe
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Andreá
authors.initials: A
authors.lastname: Fiumana
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.|Horizon Discovery, Cambridge Research Park, Waterbeach, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Scrace
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Mandy
authors.initials: M
authors.lastname: Fallowfield
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Bedford
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.affiliation: Akranim Ltd., Maidstone, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Christie
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.|Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.affiliation: Vernalis Research, Granta Park, Cambridge, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015195:Drug Design; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C000596547:V158411; D000077146:Irinotecan; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D002166:Camptothecin
keywords: Chk1; V158411; colon cancer; drug discovery; fragment