Regulating gene expression via chromatin winding and unwinding is accomplished chemically via acetylation and deacetylation events and catalyzed by a family of enzymes called histone deacetylases (HDAC).  Inhibition of these enzymes has resulted in several marketed chemotherapeutics for oncological indications.  HDAC inhibitors possess a conserved pharmacophore,  which includes binding to the catalytic zinc, resulting in high ligand binding efficiences through interacting with the catalytic zinc. However, this efficiency comes with a high cost; the commonly used metal-binding elements are mutagenic, contain electrophilic/reactive functionality with elevated risk of drug-induced liver injury, and/or contain metabolic “soft spots” that limit options for modulating pharmacokinetics. While these liabilities have not limited exploration of HDAC inhibitor therapy in an oncology setting, these are major obstacles in other areas of unmet medical need where HDAC intervention could provide clinically meaningful therapies. We sought to indentify inhibitors lacking a metal binding element in order to avoid the aforementioned liabilities.  Herein, we present the discovery and optimization of a class of such inhibitors with remarkable biochemical and cellular potency, characterization their binding mode via x-ray crystallography, and demonstrate their potential in cell based models of HIV latency reversal.<br/>

Identification of potent, selective, cell-active class 1 histone deacetylase inhibitors lacking a zinc binding group

255th National Meeting (2018)

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