Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.

中文翻译：

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组蛋白脱乙酰基酶6锌指结构域和泛素之间相互作用的小分子拮抗剂。

HDAC6抑制剂在多种癌症中具有诱人的潜力。迄今为止，HDAC6抑制剂靶向催化结构域，但靶向HDAC6独特的锌指泛素结合结构域（Zf-UBD）可能是一种有吸引力的替代策略。我们开发了X射线晶体学和生物物理测定法，以鉴定和表征能够与Zf-UBD结合并与泛素结合竞争的小分子。我们的结果揭示了HDAC6 Zf-UBD的两个相邻的可配体口袋和该域的第一个功能性配体。