Non-Aniline Histone Deacetylase Inhibitors


Technology: Inventors at MUSC have discovered a 2-(oxazol-2-yl)phenol moiety containing a novel zinc binding group (ZBG) that can be used to produce compounds that are potent histone deacetylase (HDAC) inhibitors. A series of 15 analogues with the novel ZBG have been synthesized, and exhibit selective inhibition against HDAC1 as well as HDAC 6 & HDAC10. Compound 10 possesses an IC50 value of 7.5 μM in the MV-4-11 leukemia cell line, and induces a comparable amount of acetylated histone 3 lysine 9 (H3K9) and p21Waf1/CIP1 as 0.5 μM of SAHA. Modeling of compound 10 in the active site of HDAC2 demonstrates that it has a zinc-binding pattern similar to benzamide HDAC inhibitors, but does not contain an aniline moiety that can potentially generate toxic metabolites in vivo. Additionally, the HDAC inhibitor base structure can be synthesized via a facile one-pot reaction procedure that is highly amenable to compound library development.


Overview: HDAC inhibitors have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, and are recently being investigated as possible treatments for cancers as well as parasitic and inflammatory diseases. HDACs are considered highly attractive targets for cancer drug discovery. The hyperacetylation induced by HDAC inhibitors leads to changes in gene expression and functional modifications of non-histone proteins, thereby triggering antitumor pathways. Small molecules featuring a hydroxamic acid or benzamide ZBG have been the most commonly studied HDAC inhibitors to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety and potential metabolic toxicity of the aniline portion of the benzamide HDAC inhibitors have stimulated research to discover alternative ZBGs.


Advantages: Structurally the same as benzamide HDACs without the aniline moiety that generates toxic metabolites in vivo.
Key Words: Zinc binding group, gene expression modification, cancer, histone deacetylase inhibitor, drug discovery


Publications: Li, Youxuan, and Patrick M. Woster. "Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group." MedChemComm (2015).

Inventors: Patrick M. Woster & Youxuan Li
Patent Status: US 10,000,474

MUSC-FRD Technology ID: P1504

Patent Information:
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Patrick Woster
Youxuan Li
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