1. Academic Validation
  2. Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

  • J Med Chem. 2017 Mar 23;60(6):2271-2286. doi: 10.1021/acs.jmedchem.6b01478.
Paul A Brough 1 Lisa Baker 1 Simon Bedford 1 Kirsten Brown 1 Seema Chavda 1 Victoria Chell 1 Jalanie D'Alessandro 1 Nicholas G M Davies 1 Ben Davis 1 Loic Le Strat 1 Alba T Macias 1 Daniel Maddox 1 Patrick C Mahon 1 Andrew J Massey 1 Natalia Matassova 1 Sean McKenna 1 Johannes W G Meissner 1 Jonathan D Moore 1 James B Murray 1 Christopher J Northfield 1 Charles Parry 1 Rachel Parsons 1 Stephen D Roughley 1 Terry Shaw 1 Heather Simmonite 1 Stephen Stokes 1 Allan Surgenor 1 Emma Stefaniak 1 Alan Robertson 1 Yikang Wang 1 Paul Webb 1 Neil Whitehead 1 Mike Wood 1
Affiliations

Affiliation

  • 1 Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
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.

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