Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4),Organic & Biomolecular Chemistry

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Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2017-08-24 00:00:00 , DOI: 10.1039/c7ob01584d
Mykhaylo S. Frasinyuk _{1,

2,

3,

4,

5} , Wen Zhang _{1,

2,

3,

4,

5} , Przemyslaw Wyrebek _{1,

2,

3,

4,

5} , Tianxin Yu _{1,

2,

3,

4,

5} , Xuehe Xu _{1,

2,

3,

4,

5} , Vitaliy M. Sviripa _{3,

4,

5,

6,

7} , Svitlana P. Bondarenko _{8,

9,

10} , Yanqi Xie _{1,

2,

3,

4,

5} , Huy X. Ngo _{3,

4,

5,

7,

11} , Andrew J. Morris _{2,

3,

4,

5,

12} , James L. Mohler _{5,

13,

14,

15} , Michael V. Fiandalo _{5,

13,

14,

15} , David S. Watt _{1,

2,

3,

4,

5} , Chunming Liu _{1,

2,

3,

4,

5}

Affiliation

Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the D-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.

中文翻译：

开发针对过氧化物酶体酶的抗肿瘤药：胱氨酸连接的异黄酮类化合物作为羟基类固醇17-β-脱氢酶4（HSD17B4）的抑制剂

半胱氨酸连接的异类黄酮（CLIFs）通过抑制过氧化物酶体双功能酶来抑制PC-3前列腺癌和LS174T结肠癌细胞的增殖。使用具有生物活性的生物素修饰的CLIF进行的下拉测定法确定了这些药物的靶标为双功能过氧化物酶体酶，羟基类固醇17β-脱氢酶4（HSD17B4）。使用截短版本的HSD17B4进行的其他研究表明，CLIF与HSD17B4的C末端特异性结合，并选择性抑制烯酰CoA水合酶，但不抑制D-3-羟酰基辅酶A脱氢酶活性。HSD17B4在前列腺和结肠癌组织中过表达，导致HSD17B4抑制癌细胞增殖，表明HSD17B4是潜在的生物标志物和药物靶标，CLIF是这些癌症的潜在探针或治疗剂。

更新日期：2017-09-20

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