Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors
Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors
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DOI：
10.1021/acs.jmedchem.8b00258
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发表时间：
2018-05-24
影响因子：
7.3
通讯作者：
Schapira, Matthieu
中科院分区：
文献类型：
--
作者：
de Freitas, Renato Ferreira;Harding, Rachel J.;Schapira, Matthieu
HDAC 6在募集蛋白质聚集体以进行溶酶体降解中起核心作用，并且是多发性骨髓瘤中与蛋白酶体抑制剂联合治疗的有希望的靶点。从HDAC 6的锌指泛素结合结构域（ZnF-UBD）中药理学地置换泛素是催化抑制的一种未被探索的替代方案。在这里，我们提出了HDAC 6 ZnF-UBD聚焦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进展。一个羧酸模仿泛素的C-末端，和一个扩展的芳香族系统堆叠W1182和R1155，是必要的活动。其中一种化合物诱导了结合位点的构象重塑，其中初级结合口袋打开到可用于增加效力的配体的次级口袋上。伴随着9种晶体结构的初步结构活性关系应该能够进一步优化成化学探针，以研究在多发性骨髓瘤和其他疾病中靶向HDAC 6的ZnF-UBD的优点。
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.