DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors.
DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors.
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DOI：
10.1021/acs.jmedchem.0c00545
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发表时间：
2020-10-08
影响因子：
7.3
通讯作者：
Kurosu M
中科院分区：
文献类型：
--
作者：
Mitachi K;Kansal RG;Hevener KE;Gillman CD;Hussain SM;Yun HG;Miranda-Carboni GA;Glazer ES;Clemons WM Jr;Kurosu M
卡普霉素通过靶向细菌移位酶I（MraY）显示出窄谱抗菌活性。在我们开发新的N-乙酰葡糖胺磷酸转移酶1（DPAGT 1）抑制剂的项目中，我们已经确定了卡普霉素苯氧基哌啶基苄基酰胺类似物（CPPB）抑制DPAGT 1酶，IC 50值为200 nM。尽管有很强的DPAGT 1抑制活性，CPPB对正常细胞和一系列癌细胞系没有显示出细胞毒性。然而，CPPB抑制了几种实体癌的迁移，包括胰腺癌，这些癌症需要高DPAGT 1表达以促进肿瘤进展。CPPB抑制DPAGT 1导致Snail表达水平降低，但在IC 50（DPAGT 1）浓度下不降低E-钙粘蛋白表达水平。CPPB与紫杉醇对患者源性胰腺癌PD 002的生长抑制作用显示出强烈的协同效应：紫杉醇（IC 50 1.25 μM）在0.0024-0.16 μM浓度下与0.10-2.0 μM CPPB（IC 50 35 μM）联合使用可抑制PD 002的生长。
Capuramycin displays narrow spectrum of antibacterial activity by targeting bacterial translocase I (MraY). In our program of development of new N-acetylglucosaminephosphotransferase1 (DPAGT1) inhibitor, we have identified that a capuramycin phenoxypiperidinylbenzylamide analogue (CPPB) inhibits DPAGT1 enzyme with an IC50 value of 200 nM. Despite a strong DPAGT1 inhibitory activity, CPPB does not show cytotoxicity against normal cells and a series of cancer cell lines. However, CPPB inhibits migrations of several solid cancers including pancreatic cancers that require high DPAGT1 expression in order for tumor progression. DPAGT1 inhibition by CPPB leads to a reduced expression level of Snail, but does not reduce E-cadherin expression level at the IC50 (DPAGT1) concentration. CPPB displays a strong synergistic effect with paclitaxel against growth-inhibitory action of a patient-derived pancreatic adenocarcinoma, PD002: paclitaxel (IC50 1.25 μM) inhibits growth of PD002 at 0.0024–0.16 μM in combination with 0.10–2.0 μM of CPPB (IC50 35 μM).
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影响因子：
5.2
作者：
Koga, T;Fukuoka, T;Hirota, T
通讯作者：
Hirota, T
影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1007/978-1-61779-207-6_2
发表时间：
2011-01-01
期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
11.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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