新型双靶点CK2/HDAC1抑制剂，对两种酶均具有纳摩尔级别的抑制活性。
New Dual CK2/HDAC1 Inhibitors with Nanomolar Inhibitory Activity against Both Enzymes.
作者信息
Rangasamy Loganathan, Ortín Irene, Zapico José María, Coderch Claire, Ramos Ana, de Pascual-Teresa Beatriz
机构信息
Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, Spain.
出版信息
ACS Med Chem Lett. 2020 Apr 7;11(5):713-719. doi: 10.1021/acsmedchemlett.9b00561. eCollection 2020 May 14.
Abstract
Four potent CK2 inhibitors derived from CX-4945 are described. They also provided nanomolar activity against HDAC1, therefore having promising utility as dual-target agents for cancer. The linker length between the hydroxamic acid and the CX-4945 scaffold plays an important role in dictating balanced activity against the targeted enzymes. The seven-carbon linker (compound ) was optimal for inhibition of both CK2 and HDAC1. Remarkably, showed 3.0 and 3.5 times higher inhibitory activity than the reference compounds CX-4945 (against CK2) and SAHA (against HDAC1), respectively. Compound exhibited micromolar activity in cell-based cytotoxic assays against multiple cell lines.
摘要
描述了四种源自CX-4945的强效CK2抑制剂。它们对HDAC1也具有纳摩尔活性，因此作为癌症的双靶点药物具有广阔的应用前景。异羟肟酸与CX-4945支架之间的连接子长度在决定对靶向酶的平衡活性方面起着重要作用。七碳连接子（化合物 ）对于抑制CK2和HDAC1是最佳的。值得注意的是， 分别显示出比参考化合物CX-4945（针对CK2）和SAHA（针对HDAC1）高3.0倍和3.5倍的抑制活性。化合物 在针对多种细胞系的基于细胞的细胞毒性试验中表现出微摩尔活性。
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3
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J Med Chem. 2019 Oct 24;62(20):8881-8914. doi: 10.1021/acs.jmedchem.9b00017. Epub 2019 May 28.
4
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Curr Opin Chem Biol. 2019 Jun;50:89-100. doi: 10.1016/j.cbpa.2019.03.002. Epub 2019 Apr 12.
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