title: High-Throughput Screening and Hit Validation of Extracellular-Related Kinase 5 (ERK5) Inhibitors.
abstract: The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57 617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and reassay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits. Structure-activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development. The minimum kinase binding pharmacophore was identified, and key examples demonstrated good selectivity for ERK5 over p38α kinase.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Myers
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Bawn
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Framlington Place, Newcastle University , Paul O'Gorman Building, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Bisset
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Blackburn
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Betty
authors.initials: B
authors.lastname: Cottyn
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Lauren
authors.initials: L
authors.lastname: Molyneux
authors.affiliation: Cancer Research Technology, Ltd., Discovery Laboratories, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower Street, London, WC1E 6BT, U.K.
authors.forename: Ai-Ching
authors.initials: AC
authors.lastname: Wong
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Celine
authors.initials: C
authors.lastname: Cano
authors.affiliation: School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: William
authors.initials: W
authors.lastname: Clegg
authors.affiliation: School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Harrington
authors.affiliation: The Beatson Institute for Cancer Research , Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, U.K.
authors.forename: Hing
authors.initials: H
authors.lastname: Leung
authors.affiliation: Cancer Research Technology, Ltd., Discovery Laboratories, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower Street, London, WC1E 6BT, U.K.
authors.forename: Laurent
authors.initials: L
authors.lastname: Rigoreau
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vidot
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.affiliation: Cancer Research Technology, Ltd., Discovery Laboratories, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower Street, London, WC1E 6BT, U.K.
authors.forename: Tim
authors.initials: T
authors.lastname: Hammonds
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Framlington Place, Newcastle University , Paul O'Gorman Building, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University , Newcastle upon Tyne, NE1 7RU, U.K.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D048308:Mitogen-Activated Protein Kinase 14; D048054:Mitogen-Activated Protein Kinase 7
keywords: cancer therapy; extracellular-related kinase 5 (ERK5); high-throughput screening; library; p38α kinase; structure−activity studies