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

被引：23

作者：

Brough, Paul A. ^{[1
]}

Baker, Lisa ^{[1
]}

Bedford, Simon ^{[1
]}

Brown, Kirsten ^{[1
]}

Chavda, Seema ^{[1
]}

Chell, Victoria ^{[1
]}

D'Alessandro, Jalanie ^{[1
]}

Davies, Nicholas G. M. ^{[1
]}

Davis, Ben ^{[1
]}

Le Strat, Loic ^{[1
]}

Macias, Alba T. ^{[1
]}

Maddox, Daniel ^{[1
]}

Mahon, Patrick C. ^{[1
,3
]}

Massey, Andrew J. ^{[1
]}

Matassova, Natalia ^{[1
]}

McKenna, Sean ^{[1
]}

Meissner, Johannes W. G. ^{[1
]}

Moore, Jonathan D. ^{[1
,2
]}

Murray, James B. ^{[1
]}

Northfield, Christopher J. ^{[1
]}

Parry, Charles ^{[1
]}

Parsons, Rachel ^{[1
]}

Roughley, Stephen D. ^{[1
]}

Shaw, Terry ^{[1
]}

Simmonite, Heather ^{[1
]}

Stokes, Stephen ^{[1
]}

Surgenor, Allan ^{[1
]}

Stefaniak, Emma ^{[1
]}

Robertson, Alan ^{[1
]}

Wang, Yikang ^{[1
]}

Webb, Paul ^{[1
]}

Whitehead, Neil ^{[1
]}

Wood, Mike ^{[1
]}

机构：

[1] Vernalis R&D Ltd, Granta Pk, Cambridge CB21 6GB, England

[2] Horizon Discovery, Cambridge Res Pk, Cambridge CB25 9TL, England

[3] CRT Discovery Labs, Jonas Webb Bldg,Babraham Res Campus, Cambridge CB22 3AT, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 06期

关键词：

CHEMICAL SPACE; DICHLOROACETATE; HSP90; CANCER; DISCOVERY; OPTIMIZATION; ADAPTATION; THERAPY; AZD7545; HYPOXIA;

D O I：

10.1021/acs.jmedchem.6b01478

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 E1 alpha subunit in the PC3 cancer cell line in vitro.

引用

页码：2271 / 2286

页数：16

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