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.