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<p>The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of ~ 400 client proteins, many of which contribute to oncogenesis. As a result, Hsp90 pan-inhibitors, which inhibit all four Hsp90 isoforms, have been investigated in the clinic for the treatment of cancer. Unfortunately, detrimental side effects were observed and hindered the clinical development of pan-Hsp90 inhibitors. The two most common on-target toxicities, cardio-toxicity and ocular-toxicity, have been attributed to inhibition of the Hsp90α isoform. As an alternative strategy, Hsp90β-selective inhibitors have been developed, which have shown promising anti-cancer activity in vitro and in vivo in combination with immune-checkpoint blockade therapy. This study aims to assess the potential risks of cardio-toxicity and ocular-toxicity exhibited by Hsp90β-selective inhibitors in vitro. In summary, the Hsp90β-selective <b>NDNB1182</b> was found to avoid the cardio- and ocular-toxicity typical of Hsp90 pan-inhibitors (e.g. <b>17-AAG</b>), providing a promising path toward the generation of isoform-selective Hsp90 inhibitors.</p>

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Assessment of Hsp90β-selective inhibitor safety and on-target effects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月29日

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  • Tyelor S. Reynolds,
  • Sanket J. Mishra,
  • Brian S. J. Blagg

摘要

The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of ~ 400 client proteins, many of which contribute to oncogenesis. As a result, Hsp90 pan-inhibitors, which inhibit all four Hsp90 isoforms, have been investigated in the clinic for the treatment of cancer. Unfortunately, detrimental side effects were observed and hindered the clinical development of pan-Hsp90 inhibitors. The two most common on-target toxicities, cardio-toxicity and ocular-toxicity, have been attributed to inhibition of the Hsp90α isoform. As an alternative strategy, Hsp90β-selective inhibitors have been developed, which have shown promising anti-cancer activity in vitro and in vivo in combination with immune-checkpoint blockade therapy. This study aims to assess the potential risks of cardio-toxicity and ocular-toxicity exhibited by Hsp90β-selective inhibitors in vitro. In summary, the Hsp90β-selective NDNB1182 was found to avoid the cardio- and ocular-toxicity typical of Hsp90 pan-inhibitors (e.g. 17-AAG), providing a promising path toward the generation of isoform-selective Hsp90 inhibitors.