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
  • 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.