Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 5, Issue 4, Pages 207-215Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.1c00243
Keywords
acute kidney injury; histone deacetylase inhibitor; zebrafish; HDAC8; kidney organoids; PCI-34051
Categories
Funding
- DoD [W81XWH-17-0610]
- NIH [2R01 DK069403, 2UC2 DK126122]
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This study evaluated the potential of selective HDAC8 inhibitors as a therapeutic approach for AKI. The researchers showed through various experimental models that these inhibitors are effective, with the compound PCI-34051 showing promise in a rodent AKI model.
Acute kidney injury (AKI), a sudden loss of kidney function, is a common and serious condition for which there are no approved specific therapies. While there are multiple approaches to treat the underlying causes of AKI, no targets have been clinically validated. Here, we assessed a series of potent, selective competitive inhibitors of histone deacetylase 8 (HDAC8), a promising therapeutic target in an AKI setting. Using biochemical assays, zebrafish AKI phenotypic assays, and human kidney organoid assays, we show that selective HDAC8 inhibitors can lead to efficacy in increasingly stringent models. One of these, PCI-34051, was efficacious in a rodent model of AKI, further supporting the potential for HDAC8 inhibitors and, in particular, this scaffold as a therapeutic approach to AKI.
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