Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
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Authors
Cheeseman, MD
Chessum, NEA
Rye, CS
Pasqua, AE
Tucker, MJ
Wilding, B
Evans, LE
Lepri, S
Richards, M
Sharp, SY
Ali, S
Rowlands, M
O'Fee, L
Miah, A
Hayes, A
Henley, AT
Powers, M
Te Poele, R
De Billy, E
Pellegrino, L
Raynaud, F
Burke, R
van Montfort, RLM
Eccles, SA
Workman, P
Jones, K
Chessum, NEA
Rye, CS
Pasqua, AE
Tucker, MJ
Wilding, B
Evans, LE
Lepri, S
Richards, M
Sharp, SY
Ali, S
Rowlands, M
O'Fee, L
Miah, A
Hayes, A
Henley, AT
Powers, M
Te Poele, R
De Billy, E
Pellegrino, L
Raynaud, F
Burke, R
van Montfort, RLM
Eccles, SA
Workman, P
Jones, K
Document Type
Journal Article
Date
2017-01-12
Date Accepted
2016-11-23
Abstract
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 SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.
Citation
Journal of medicinal chemistry, 2017, 60 (1), pp. 180 - 201
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Collections
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 3
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design
Medicinal Chemistry 3
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design