Daniel Kevin B, Sullivan Eric D, Chen Yao, Chan Joshua C, Jennings Patricia A, Fierke Carol A, Cohen Seth M
†Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
J Med Chem. 2015 Jun 11;58(11):4812-21. doi: 10.1021/acs.jmedchem.5b00539. Epub 2015 Jun 2.
Histone deacetylase inhibitors (HDACi) target abnormal epigenetic states associated with a variety of pathologies, including cancer. Here, the development of a prodrug of the canonical broad-spectrum HDACi suberoylanilide hydroxamic acid (SAHA) is described. Although hydroxamic acids are utilized universally in the development of metalloenzyme inhibitors, they are considered to be poor pharmacophores with reduced activity in vivo. We developed a prodrug of SAHA by appending a promoiety, sensitive to thiols, to the hydroxamic acid warhead (termed SAHA-TAP). After incubation of SAHA-TAP with an HDAC, the thiol of a conserved HDAC cysteine residue becomes covalently tagged with the promoiety, initiating a cascade reaction that leads to the release of SAHA. Mass spectrometry and enzyme kinetics experiments validate that the cysteine residue is covalently appended with the TAP promoiety. SAHA-TAP demonstrates cytotoxicity activity against various cancer cell lines. This strategy represents an original prodrug design with a dual mode of action for HDAC inhibition.
组蛋白去乙酰化酶抑制剂（HDACi）针对与包括癌症在内的多种病症相关的异常表观遗传状态。在此，描述了经典广谱HDACi辛二酰苯胺异羟肟酸（SAHA）的一种前药的开发。虽然异羟肟酸在金属酶抑制剂的开发中被普遍使用，但它们被认为是体内活性降低的不良药效基团。我们通过将对硫醇敏感的前体部分连接到异羟肟酸弹头（称为SAHA-TAP）上，开发了一种SAHA前药。SAHA-TAP与HDAC孵育后，保守的HDAC半胱氨酸残基的硫醇会与前体部分共价标记，引发级联反应，导致SAHA释放。质谱和酶动力学实验证实半胱氨酸残基与TAP前体部分共价连接。SAHA-TAP对多种癌细胞系表现出细胞毒性活性。该策略代表了一种具有HDAC抑制双重作用模式的原创前药设计。
