title: The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.
abstract: CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Mike I
authors: MI
authors: Walton
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Paul D
authors: PD
authors: Eve
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Angela
authors: A
authors: Hayes
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Alan T
authors: AT
authors: Henley
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Melanie R
authors: MR
authors: Valenti
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Alexis K
authors: AK
authors: De Haven Brandon
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Gary
authors: G
authors: Box
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Kathy J
authors: KJ
authors: Boxall
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Matthew
authors: M
authors: Tall
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Karen
authors: K
authors: Swales
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Thomas P
authors: TP
authors: Matthews
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Tatiana
authors: T
authors: McHardy
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Michael
authors: M
authors: Lainchbury
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: James
authors: J
authors: Osborne
authors: Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle Upon Tyne, UK.
authors: Jill E
authors: JE
authors: Hunter
authors: Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle Upon Tyne, UK.
authors: Neil D
authors: ND
authors: Perkins
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: G Wynne
authors: GW
authors: Aherne
authors: Sareum Ltd, Cambridge, UK.
authors: John C
authors: JC
authors: Reader
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Florence I
authors: FI
authors: Raynaud
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Suzanne A
authors: SA
authors: Eccles
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
authors: Ian
authors: I
authors: Collins
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.|School of Biosciences, University of Kent, Canterbury, Kent, UK.
authors: Michelle D
authors: MD
authors: Garrett
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000187:drug effects* / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C000612152:CCT245737; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D003841:Deoxycytidine; D000077146:Irinotecan; D015761:4-Aminopyridine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D016283:Proto-Oncogene Proteins p21(ras); D002166:Camptothecin; D000093542:Gemcitabine
keywords: CCT245737; CHK1; antitumor activity; biomarker assay; pharmacology