PDHK – application of off-rate screening (ORS)2018-12-17T09:33:53+00:00

Project Description

Pyruvate dehydrogenase kinase (PDHK) – application of off-rate screening in the identification of novel pan-isoform inhibitors

Brough et al., J. Med. Chem. 2017

Moore et al., Oncotarget 2014

Libraries of non-purified 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 optimisation identified selective, sub-100 nM inhibitors of the enzyme, such as VER-246808, which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.

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