Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
Matthew D CheesemanNicola E A ChessumCarl S RyeA Elisa PasquaMichael J TuckerBirgit WildingLindsay E EvansSusan LepriMeirion RichardsSwee Y SharpSalyha AliMartin RowlandsLisa O'FeeAsadh MiahAngela HayesAlan T HenleyMarissa PowersRobert Te PoeleEmmanuel De BillyLoredana PellegrinoFlorence RaynaudRosemary BurkeRob L M van MontfortSuzanne A EcclesPaul WorkmanKeith JonesPublished in: Journal of medicinal chemistry (2016)
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.
Keyphrases
- heat shock
- high throughput
- drug discovery
- transcription factor
- heat stress
- living cells
- small molecule
- quantum dots
- heat shock protein
- single cell
- endothelial cells
- mass spectrometry
- oxidative stress
- stem cells
- genome wide
- dna binding
- cell therapy
- fluorescent probe
- single molecule
- bone marrow
- induced pluripotent stem cells
- capillary electrophoresis