针对胃癌的强效和特异性MTH1抑制剂。,Cell Death & Disease

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针对胃癌的强效和特异性MTH1抑制剂。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-06-04 , DOI: 10.1038/s41419-019-1665-3
Wenjuan Zhou _{1,

2} , Liying Ma ₁ , Jing Yang ₁ , Hui Qiao ₁ , Lingyu Li ₁ , Qian Guo ₁ , Jinlian Ma ₁ , Lijuan Zhao ₁ , Junwei Wang ₁ , Guozhong Jiang ₃ , Xiangbin Wan ₄ , Mariusz Adam Goscinski ₅ , Lina Ding ₁ , Yichao Zheng ₁ , Wencai Li ₃ , Hongmin Liu ₁ , Zhenhe Suo ₂ , Wen Zhao ₁

Affiliation

据报道，人mutT同系物1（MTH1）是氧化的dNTP池消毒剂，在各种恶性肿瘤中高表达。然而，MTH1在胃癌中的致癌作用仍有待确定。在当前的研究中，我们发现MTH1在人胃癌组织和细胞中过表达。使用体外MTH1抑制剂筛选系统，筛选了我们实验室中可用的化合物，并首先发现了含有5-氰基-6-苯基嘧啶结构的小分子对MTH1尤其是化合物MI-743的IC50表现出了强力和特异性的抑制作用。＝ 91.44±1.45nM。分子对接和靶标参与实验均证明MI-743可以直接与MTH1结合。此外，MI-743不仅可以抑制多达16种癌细胞系的细胞增殖，特别是胃癌细胞HGC-27和MGC-803，还可以明显诱导MTH1相关的8-oxo-dG积累和DNA损伤。此外，MI-743处理还显着抑制了裸鼠中注射MGC-803细胞衍生的异种移植肿瘤的生长。重要的是，在这两个胃癌细胞中，siRNA敲除MTH1表现出相似的发现。我们的发现表明，MTH1在人胃癌组织和细胞系中高表达。具有5-氰基-6-苯基嘧啶结构的小分子MI-743可以作为靶向胃癌治疗中过度表达的MTH1的新型先导化合物。MI-743处理也显着抑制了通过注射MGC-803细胞在裸鼠中产生的异种移植肿瘤的生长。重要的是，在这两个胃癌细胞中，siRNA敲除MTH1表现出相似的发现。我们的发现表明，MTH1在人胃癌组织和细胞系中高表达。具有5-氰基-6-苯基嘧啶结构的小分子MI-743可以作为靶向胃癌治疗中过度表达的MTH1的新型先导化合物。MI-743处理也显着抑制了通过注射MGC-803细胞在裸鼠中产生的异种移植肿瘤的生长。重要的是，在这两个胃癌细胞中，siRNA敲除MTH1表现出相似的发现。我们的发现表明，MTH1在人胃癌组织和细胞系中高表达。具有5-氰基-6-苯基嘧啶结构的小分子MI-743可以作为靶向胃癌治疗中过度表达的MTH1的新型先导化合物。

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Potent and specific MTH1 inhibitors targeting gastric cancer.

Human mutT homolog 1(MTH1), the oxidized dNTP pool sanitizer enzyme, has been reported to be highly expressed in various malignant tumors. However, the oncogenic role of MTH1 in gastric cancer remains to be determined. In the current study, we found that MTH1 was overexpressed in human gastric cancer tissues and cells. Using an in vitro MTH1 inhibitor screening system, the compounds available in our laboratory were screened and the small molecules containing 5-cyano-6-phenylpyrimidine structure were firstly found to show potently and specifically inhibitory effect on MTH1, especially compound MI-743 with IC50 = 91.44 ± 1.45 nM. Both molecular docking and target engagement experiments proved that MI-743 can directly bind to MTH1. Moreover, MI-743 could not only inhibit cell proliferation in up to 16 cancer cell lines, especially gastric cancer cells HGC-27 and MGC-803, but also significantly induce MTH1-related 8-oxo-dG accumulation and DNA damage. Furthermore, the growth of xenograft tumours derived by injection of MGC-803 cells in nude mice was also significantly inhibited by MI-743 treatment. Importantly, MTH1 knockdown by siRNA in those two gastric cancer cells exhibited the similar findings. Our findings indicate that MTH1 is highly expressed in human gastric cancer tissues and cell lines. Small molecule MI-743 with 5-cyano-6-phenylpyrimidine structure may serve as a novel lead compound targeting the overexpressed MTH1 for gastric cancer treatment.

更新日期：2019-06-04

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