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.
Highlights
Despite the recent extraordinary progress seen in cancer therapy using molecularly targeted drugs, the disease commonly remains resistant to effective long-term treatment
To observe HSF1-mediated transcription in an in vitro setting, the HSF1 pathway is activated by a validated heat shock protein 90 (HSP90) inhibitor,19 or another form of external stress,20 which initiates the heat shock response
Several HSF1-mediated HSP72 induction inhibitors have been discovered via this method with different proposed molecular mechanisms of action (Figure 1)
Summary
Despite the recent extraordinary progress seen in cancer therapy using molecularly targeted drugs, the disease commonly remains resistant to effective long-term treatment. Even when excellent responses to drugs are initially observed, resistance is almost inevitable and patients are left with few treatment options as the discovery of targeted therapies in oncology has focused on relatively few protein families.. Even when excellent responses to drugs are initially observed, resistance is almost inevitable and patients are left with few treatment options as the discovery of targeted therapies in oncology has focused on relatively few protein families.2 To break this cycle and expand the treatment options for cancer patients, new approaches are needed to discover novel druggable protein targets.. Polypharmacology is often observed with small molecules and structurally related protein families; this can be crucial for efficacy and is perfectly compatible with a phenotypic screening approach.
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