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Donna Huryn’s Research on HDAC8 Inhibitors Published in BMCL | ATLAS-D2K Center


Donna Huryn's Research on HDAC8 Inhibitors Published in BMCL

Jun 5, 2024

We are excited to announce a new publication from the ReBuilding a Kidney (RBK) consortium - care of Donna Huryn (University of Pennsylvania) - that provides important insights that could guide future research and development efforts aimed at enhancing the therapeutic potential of HDAC8 inhibitors.

Replacement of the hydroxamic acid group in the selective HDAC8 inhibitor PCI-34051

Authors: Keith Long, David A. Close, Paul A. Johnston, Donna M. Huryn Journal: Bioorganic & Medicinal Chemistry Letters DOI: 


PCI-34051 is a valuable tool to interrogate the therapeutic effects of selective inhibition of HDAC8. However, it has not advanced to clinical trials, perhaps due to poor PK or off-target effects. We hypothesized that the presence of a hydroxamic acid (HA) group in PCI-34051 contributed to its lack of advancement. Therefore, we replaced the HA in the PCI-34051 scaffold with a series of moieties that have the potential to bind to Zn and evaluated their activity in a HDAC8 assay. Surprisingly, none of the replacements effectively mimicked the HA, and analogs lost significant potency. Evaluation of the analogs’ affinity to Zn indicated that none had affinity for Zn within the same range as the HA. These studies point to the difficulty in the application of bioisosteric replacements for Zn binding motifs.

You can view all of RBK’s publications here!