Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.
Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.
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DOI：
10.1093/nar/gks189
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发表时间：
2012-07
影响因子：
14.9
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Jayathilaka N;Han A;Gaffney KJ;Dey R;Jarusiewicz JA;Noridomi K;Philips MA;Lei X;He J;Ye J;Gao T;Petasis NA;Chen L
改变细胞表观遗传状态的酶为各种疾病的治疗提供了有吸引力的靶标。然而，表观遗传调节剂的治疗开发在很大程度上仅限于直接靶向酶家族多个成员中保守的催化活性位点，这使机制研究和药物开发变得复杂。IIa类组蛋白脱乙酰基酶（HDAC）是一组表观遗传酶，其依赖于与肌细胞增强因子-2（MEF 2）的相互作用来将其募集到特定的基因组位点。靶向这种相互作用提供了抑制这类HDAC的替代方法。我们已经使用结构和功能的方法来鉴定和表征一组通过阻断其与DNA上的MEF 2的相互作用而间接靶向IIa类HDAC的小分子。我们还表明，小分子阻断了IIa类HDAC向MEF 2靶向基因的募集，以增强这些靶点的表达。这些化合物可用作体内研究MEF 2和IIa类HDAC的工具，并作为药物开发的先导。
Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and 19F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development.
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