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Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Jan 12; Vol. 60 (1), pp. 180-201. Date of Electronic Publication: 2016 Dec 22. - Publication Year :
- 2017
-
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.
- Subjects :
- Administration, Oral
Amides administration & dosage
Amides pharmacology
Biological Availability
Carbon-13 Magnetic Resonance Spectroscopy
Dioxygenases
Drug Discovery
Heat Shock Transcription Factors
Ligands
Proton Magnetic Resonance Spectroscopy
Quinolines administration & dosage
Quinolines pharmacology
Spectrometry, Mass, Electrospray Ionization
Amides chemistry
Carrier Proteins chemistry
DNA-Binding Proteins chemistry
Nuclear Proteins chemistry
Quinolines chemistry
Transcription Factors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28004573
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01055