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

• Published in: Journal of medicinal chemistry 2017-03, Vol.60 (6), p.2271-2286
• Main Authors: Brough, Paul A, Baker, Lisa, Bedford, Simon, Brown, Kirsten, Chavda, Seema, Chell, Victoria, D’Alessandro, Jalanie, Davies, Nicholas G. M, Davis, Ben, Le Strat, Loic, Macias, Alba T, Maddox, Daniel, Mahon, Patrick C, Massey, Andrew J, Matassova, Natalia, McKenna, Sean, Meissner, Johannes W. G, Moore, Jonathan D, Murray, James B, Northfield, Christopher J, Parry, Charles, Parsons, Rachel, Roughley, Stephen D, Shaw, Terry, Simmonite, Heather, Stokes, Stephen, Surgenor, Allan, Stefaniak, Emma, Robertson, Alan, Wang, Yikang, Webb, Paul, Whitehead, Neil, Wood, Mike
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Cell Line, Tumor; Drug Design; HSP90 Heat-Shock Proteins - metabolism; Humans; Male; Models, Molecular; Phosphorylation - drug effects; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Protein Isoforms - metabolism; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01478

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, k d) 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.