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Validation of HDAC8 Inhibitors as Drug Discovery Starting Points to Treat Acute Kidney Injury.


ABSTRACT: 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.

SUBMITTER: Long K 

PROVIDER: S-EPMC9003639 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Validation of HDAC8 Inhibitors as Drug Discovery Starting Points to Treat Acute Kidney Injury.

Long Keith K   Vaughn Zoe Z   McDaniels Michael David MD   Joyasawal Sipak S   Przepiorski Aneta A   Parasky Emily E   Sander Veronika V   Close David D   Johnston Paul A PA   Davidson Alan J AJ   de Caestecker Mark M   Hukriede Neil A NA   Huryn Donna M DM  

ACS pharmacology & translational science 20220316 4


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 orga  ...[more]

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