Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
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DOI：
10.1038/nbt.1759
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发表时间：
2011-03-01
影响因子：
46.9
通讯作者：
Drewes, Gerard
中科院分区：
文献类型：
--
作者：
Bantscheff, Marcus;Hopf, Carsten;Drewes, Gerard
具有抗癌和抗炎特性的选择性组蛋白脱乙酰酶（HDAC）抑制剂的开发在很大程度上仍然具有挑战性，这是由于难以探测小分子与兆道尔顿蛋白质复合物的相互作用。亲和捕获和定量质谱的组合揭示了16种HDAC抑制剂靶向由ELM-SANT结构域亚基构建的多个HDAC复合物的选择性，包括一种新型的有丝分裂脱乙酰酶复合物（MiDAC）。抑制剂根据其靶谱聚集，其中氨基苯甲酰胺与HDAC NCoR复合物的结合比与HDAC Sin 3复合物的结合更强。我们确定了几个非HDAC目标的异羟肟酸抑制剂。具有不同特征的HDAC抑制剂对下游靶标具有相应的不同作用。我们还将抗炎药bufexamac确定为IIb类（HDAC 6，HDAC 10）HDAC抑制剂。我们的方法能够发现新的靶标和抑制剂，并表明HDAC抑制剂的选择性应在HDAC复合物的背景下进行评估，而不是纯化的催化亚基。
The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits.