Fragment-based discovery of HSP70 inhibitors
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Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and are often associated with metastasis and poor prognosis. Dual silencing of two isoforms, HSP72 and HSC70, using siRNA has shown tumour specific apoptosis. However, it has proved difficult to develop drug-like small molecule inhibitors of HSP70s by traditional methods due to the flexible and hydrophilic nature of the ATP binding site and its high affinity for natural nucleotides. The aim of this work was to identify novel inhibitors of HSP70 using fragment-based drug discovery methods in two parallel approaches. The first approach focused on the validation of a cryptic, secondary binding site in HSP70 that had been identified by a fragment screen. Multiple methods were used for fragment validation including the synthesis of more soluble fragment analogues and subsequent testing by Surface Plasmon Resonance (SPR). Ligand-observed NMR was used as a orthogonal method to successfully confirm binding. A virtual high-throughput screen against this novel site was carried out by our collaborators to find new hit matter. These compounds were tested by SPR and 11 new fragment hits were identified. As the properties of this novel binding site in HSP70 differ from the ATP binding site it may offer the opportunity to develop inhibitors of HSP70 with better physiochemical properties. The second approach focused on the development of a quinazoline hit fragment that binds in the ATP binding site of HSP70. Non-nucleotide inhibitors were designed and observed to bind in the phosphate binding region for the first time. Replacement of the quinazoline ring with a naphthyridine, cinnoline, quinoline and pyrimidine cores was also investigated as well as various substitutions around the quinazoline ring. As well as increasing the potency of the quinazoline hit, these compounds have improved our understanding of the nature and flexibility of the ATP binding pocket of HSP70.
Medicinal Chemistry 2
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