Related Experiment Video
Updated: May 4, 2026
Retinal Pathophysiological Evaluation in a Rat Model
Published on: May 6, 2022
Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs
Chisako Kanamaru1, Yuichiro Yamada, Shuji Hayashi
1Research Division, Chugai Pharmaceutical Co., Ltd.
Abstract:
Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.
Insights
Heat shock protein 90 (Hsp90) inhibition can cause retinal toxicity. Two distinct Hsp90 inhibitors induced visual and electroretinographic abnormalities in dogs, suggesting Hsp90 inhibitors require ocular safety evaluations.
Area of Science:
- Oncology
- Pharmacology
- Ophthalmology
Background:
- Heat shock protein 90 (Hsp90) is crucial for oncogenic protein folding and survival.
- Hsp90 inhibitors are promising anticancer agents, with several in clinical trials.
- Understanding Hsp90 inhibitor toxicity is vital for patient safety.
Purpose of the Study:
- To evaluate the systemic toxicity of two distinct Hsp90 inhibitors, CH5164840 and CH5449302, in beagle dogs.
- To investigate potential ocular toxicity associated with Hsp90 inhibition.
- To determine if retinal toxicity is a class effect of Hsp90 inhibitors.
Main Methods:
- Oral administration of CH5164840 and CH5449302 to beagle dogs.
- Clinical observations for systemic toxicity and visual disturbances.
- Ophthalmological examinations, including pupillary light reflex assessment.
- Electroretinography (ERG) to evaluate retinal function.
- Histopathological examination of ocular tissues.
Main Results:
- CH5164840 induced clinical signs of visual disorder, abnormal ERG, and retinal histopathology.
- CH5449302, despite no clinical visual symptoms, showed similar ERG abnormalities and retinal changes.
- Retinal toxicity occurred at earlier stages or lower doses than other toxicities for both compounds.
- Ocular abnormalities were consistent with photoreceptor and outer nuclear layer damage.
Conclusions:
- Two structurally distinct Hsp90 inhibitors induce retinal toxicity in dogs.
- Hsp90 inhibition is likely to cause retinal toxicity, a potential class effect.
- Detailed ocular examinations are recommended for preclinical and clinical safety assessments of Hsp90 inhibitors.
