Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen

被引：44

作者：

Cheeseman, Matthew D. ^{[1
]}

Chessum, Nicola E. A. ^{[1
]}

Rye, Carl S. ^{[1
]}

Pasqua, A. Elisa ^{[1
]}

Tucker, Michael J. ^{[1
]}

Wilding, Birgit ^{[1
]}

Evans, Lindsay E. ^{[1
]}

Lepri, Susan ^{[1
]}

Richards, Meirion ^{[1
]}

Sharp, Swee Y. ^{[1
]}

Ali, Salyha ^{[1
,2
]}

Rowlands, Martin ^{[1
]}

O'Fee, Lisa ^{[1
]}

Miah, Asadh ^{[1
]}

Hayes, Angela ^{[1
]}

Henley, Alan T. ^{[1
]}

Powers, Marissa ^{[1
]}

te Poele, Robert ^{[1
]}

De Billy, Emmanuel ^{[1
]}

Pellegrino, Loredana ^{[1
]}

Raynaud, Florence ^{[1
]}

Burke, Rosemary ^{[1
]}

van Montfort, Rob L. M. ^{[1
,2
]}

Eccles, Suzanne A. ^{[1
]}

Workman, Paul ^{[1
]}

Jones, Keith ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Canc Therapeut Unit, London SW7 3RP, England

[2] Inst Canc Res, Div Struct Biol, London SW7 3RP, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 01期

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; CANCER DRUG-RESISTANCE; HUMAN OVARIAN-CANCER; IN-VITRO; TARGET IDENTIFICATION; HALF-LIFE; INHIBITOR; PROTEIN; EXPRESSION; COMPOUND;

D O I：

10.1021/acs.jmedchem.6b01055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell:based SAP. and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.

引用

页码：180 / 201

页数：22

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