Heat Shock Proteins and Stress by Alexzander A. A. Asea & Punit Kaur

Author:Alexzander A. A. Asea & Punit Kaur
Language: eng
Format: epub
ISBN: 9783319907253
Publisher: Springer International Publishing

A number of cell based assays relevant to cancer and neurodegenerative diseases were developed for confirming cytotoxicity of tumor cells (for HSF1 inhibitor screening) or cytoprotection of neuronal cells (for HSF1 activator screening). The details and related publications are listed in Table 8.2.5)MOA study of HSF1 activators

In our practice, MOA study was performed in parallel with SAR of lead candidates. The goal was to obtain a clinical candidate with understanding of its MOA. As stated earlier, the complex mechanisms of HSF1 regulation at the posttranslational level make it difficult for target deconvolution. For the case of HSF1 activators, our understanding of compound induced HSF1 activation process is extremely limited. Figure 8.6(A)~8.6(D) demonstrate the chemical structures of three selected lead compounds. These compounds have 5~40 μM potency in HSF1 granule assay (Zhang et al. 2009a; Zhou et al. 2009b; Zhou et al. 2009c). After treatment with these compounds, prolonged activation of HSF1, along with amplified HSP expression, was confirmed in the heat shocked cells. Importantly, no effects were observed in cells without stress. As a result, potent cytoprotective activities were recorded in various disease relevant cell based models (Table 8.2), such as transiently or stably transfected poly Q-Htt models (relevant to Huntington’s disease), rotenone neuronal cytotoxicity model (relevant to Parkinson’s disease), MG-132 cytotoxicity model (relevant to ER stress), oxygen glucose deprivation model (relevant to ischemia and stroke), etc. Multiple HSF1 knockdown studies supported the notion of HSF1 dependency for compound induced cytoprotection in different cell based systems, although no individual cellular target was successfully identified (Zhang et al. 2009a).

SAR and lead optimization led to the discovery of a pyrimido[5,4-e] [1,2,4]triazine-5,7(1H,6H)-dione derivative (Compound 4A-1, Fig. 8.6(A)), which has a sub-micromolar potency (EC50 value of 0.41 μM) in the rotenone neuronal cytotoxicity model (Zhou et al. 2009c). The results from rat liver microsome study demonstrated that this compound has favorable metabolic stability with medium-high aqueous solubility. The good drug-like property makes this compound a potential clinical candidate in the treatment of Parkinson’s disease (Zhou et al. 2009a).6)MOA study of HSF1 inhibitors

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