title: Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.
abstract: Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Paul A
authors.identifier: 0000-0001-7789-8101
authors.initials: PA
authors.lastname: Brough
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Simon
authors.initials: S
authors.lastname: Bedford
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Brown
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Seema
authors.initials: S
authors.lastname: Chavda
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Victoria
authors.initials: V
authors.lastname: Chell
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Jalanie
authors.initials: J
authors.lastname: D'Alessandro
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Nicholas G M
authors.initials: NG
authors.lastname: Davies
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Strat
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Alba T
authors.initials: AT
authors.lastname: Macias
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Daniel
authors.initials: D
authors.lastname: Maddox
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Mahon
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Natalia
authors.initials: N
authors.lastname: Matassova
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Sean
authors.initials: S
authors.lastname: McKenna
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Johannes W G
authors.initials: JW
authors.lastname: Meissner
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: James B
authors.initials: JB
authors.lastname: Murray
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Northfield
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Charles
authors.initials: C
authors.lastname: Parry
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Rachel
authors.initials: R
authors.lastname: Parsons
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Stephen D
authors.identifier: 0000-0003-0683-5693
authors.initials: SD
authors.lastname: Roughley
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Terry
authors.initials: T
authors.lastname: Shaw
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Heather
authors.initials: H
authors.lastname: Simmonite
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Stokes
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Allan
authors.initials: A
authors.lastname: Surgenor
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Emma
authors.initials: E
authors.lastname: Stefaniak
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Alan
authors.initials: A
authors.lastname: Robertson
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Yikang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Neil
authors.initials: N
authors.lastname: Whitehead
authors.affiliation: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases