Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
Date
2017-01-12ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Amides
Quinolines
Carrier Proteins
DNA-Binding Proteins
Nuclear Proteins
Transcription Factors
Ligands
Spectrometry, Mass, Electrospray Ionization
Administration, Oral
Biological Availability
Drug Discovery
Proton Magnetic Resonance Spectroscopy
Carbon-13 Magnetic Resonance Spectroscopy
Heat Shock Transcription Factors
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 3
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design
Language
eng
Date accepted
2016-11-23
License start date
2017-01
Citation
Journal of medicinal chemistry, 2017, 60 (1), pp. 180 - 201
Publisher
AMER CHEMICAL SOC