Identification and Structure–Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors,Journal of Medicinal Chemistry

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Identification and Structure–Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-05-09 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00258
Renato Ferreira de Freitas ₁ , Rachel J. Harding ₁ , Ivan Franzoni ₂ , Mani Ravichandran ₁ , Mandeep K. Mann ₁ , Hui Ouyang ₁ , Mark Lautens ₂ , Vijayaratnam Santhakumar ₁ , Cheryl H. Arrowsmith _{1,

3} , Matthieu Schapira _{1,

4}

Affiliation

HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure–activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

中文翻译：

HDAC6锌指泛素结合域抑制剂的鉴定及其构效关系

HDAC6在募集溶酶体降解的蛋白质聚集体中起着核心作用，并且是与蛋白酶体抑制剂联合治疗多发性骨髓瘤的有希望的靶标。从HDAC6的锌指遍在蛋白结合结构域（ZnF-UBD）药理学上取代遍在蛋白是催化抑制作用的未开发的替代方法。在这里，我们介绍了以HDAC6 ZnF-UBD为重点的化学系列的发现及其从虚拟筛选命中到低微摩尔抑制剂的发展。模仿泛素的C末端末端的羧酸盐以及与W1182和R1155堆叠在一起的扩展的芳香族系统对于活性是必需的。其中一种化合物诱导了结合位点的构象重塑，其中主要的结合口袋向可配体的次要口袋开放，可用于提高效力。

更新日期：2018-05-09

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