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

2017; American Chemical Society; Volume: 60; Issue: 6 Linguagem: Inglês

10.1021/acs.jmedchem.6b01478

1520-4804

Paul A. Brough, Lisa Baker, Simon T. Bedford, Kirsten Brown, Seema Chavda, Victoria Chell, Jalanie D’Alessandro, Nicholas G. Davies, Ben Davis, Loic Le Strat, Alba T. Macias, Daniel Maddox, Patrick C. Mahon, Andrew J. Massey, Natalia Matassova, Sean A. McKenna, Johannes Meissner, Jonathan D. Moore, James B. Murray, Christopher J. Northfield, Charles Parry, Rachel Parsons, Stephen D. Roughley, T. Shaw, Heather Simmonite, S.P. Stokes, A.E. Surgenor, Emma Stefaniak, Alan Robertson, Yikang Wang, Paul Webb, N.E. Whitehead, Mike Wood,

Biochemical Acid Research Studies

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.