Assessment of Hsp90β-selective inhibitor safety and on-target effects
Abstract 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 trea...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-86647-y |
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| author | Tyelor S. Reynolds Sanket J. Mishra Brian S. J. Blagg |
| author_facet | Tyelor S. Reynolds Sanket J. Mishra Brian S. J. Blagg |
| author_sort | Tyelor S. Reynolds |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-ba66d69c0fba4373a2d429dff6401a60 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-ba66d69c0fba4373a2d429dff6401a602025-02-02T12:23:39ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-025-86647-yAssessment of Hsp90β-selective inhibitor safety and on-target effectsTyelor S. Reynolds0Sanket J. Mishra1Brian S. J. Blagg2Department of Chemistry and Biochemistry, The University of Notre DameDepartment of Chemistry and Biochemistry, The University of Notre DameDepartment of Chemistry and Biochemistry, The University of Notre DameAbstract 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.https://doi.org/10.1038/s41598-025-86647-yHsp90β-selective inhibitorCancer therapySafety assessmentCardiotoxicityOcular-toxicity |
| spellingShingle | Tyelor S. Reynolds Sanket J. Mishra Brian S. J. Blagg Assessment of Hsp90β-selective inhibitor safety and on-target effects Scientific Reports Hsp90β-selective inhibitor Cancer therapy Safety assessment Cardiotoxicity Ocular-toxicity |
| title | Assessment of Hsp90β-selective inhibitor safety and on-target effects |
| title_full | Assessment of Hsp90β-selective inhibitor safety and on-target effects |
| title_fullStr | Assessment of Hsp90β-selective inhibitor safety and on-target effects |
| title_full_unstemmed | Assessment of Hsp90β-selective inhibitor safety and on-target effects |
| title_short | Assessment of Hsp90β-selective inhibitor safety and on-target effects |
| title_sort | assessment of hsp90β selective inhibitor safety and on target effects |
| topic | Hsp90β-selective inhibitor Cancer therapy Safety assessment Cardiotoxicity Ocular-toxicity |
| url | https://doi.org/10.1038/s41598-025-86647-y |
| work_keys_str_mv | AT tyelorsreynolds assessmentofhsp90bselectiveinhibitorsafetyandontargeteffects AT sanketjmishra assessmentofhsp90bselectiveinhibitorsafetyandontargeteffects AT briansjblagg assessmentofhsp90bselectiveinhibitorsafetyandontargeteffects |