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J Med Chem. 2017 Mar 23;60(6):2271-2286. doi: 10.1021/acs.jmedchem.6b01478. Epub 2017 Feb 15.

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

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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.

PMID:
28199108
DOI:
10.1021/acs.jmedchem.6b01478
[Indexed for MEDLINE]

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