90437-23-3Relevant academic research and scientific papers
Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
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
supporting information, p. 2271 - 2286 (2017/04/03)
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.
