Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.
Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.
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DOI：
10.1002/cmdc.202000137
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发表时间：
2020-06-17
期刊：
影响因子：
3.4
通讯作者：
McInnes C
中科院分区：
文献类型：
--
作者：
Baxter M;Chapagai D;Craig S;Hurtado C;Varghese J;Nurmemmedov E;Wyatt MD;McInnes C
PLK 1的Polo盒结构域（PBD）决定有丝分裂底物识别和亚细胞定位。由于PLK 3的肿瘤抑制作用，需要选择性靶向PLK 1的化合物。PBD磷酸肽结合基序的结构-活性分析已经确定了有效的肽，其描绘了非肽抑制剂模拟所需的决定因素，并提供了对PLK 1 PBD抑制剂选择性的结构基础的见解。通过REPLACE获得的片段连接抑制肽（FLIP）已被优化以增强体外结合，并对肽和肽模拟物对PLK 1与3的选择性进行了系统分析。此外，这些更像药物的非ATP竞争性抑制剂在细胞环境中具有靶向接合，如通过在热位移测定中PLK 1的稳定化和通过PLK 1的靶点TCTP的磷酸化的抑制所证明的。在表达突变体PLK 1的细胞中的研究表明，这些突变体对PBD抑制剂敏感，但对临床研究的ATP竞争性化合物具有显著抗性。这些结果提供了靶向PBD结合位点的进一步有效性，并向对ATP抑制剂具有抗性的肿瘤具有活性的PBD抑制剂发展。PLK 1的polo-box结构域（PBD）决定有丝分裂底物的识别和定位。通过REPLACE获得的化合物已被优化以增强结合，并对PLK 1与PLK 3的选择性进行系统分析。这些更像药物的抑制剂在细胞热位移测定中具有靶向接合，并且通过抑制PLK 1的靶点TCTP的磷酸化。结果进一步证明了靶向PBD结合位点和进展抑制剂对ATP抑制剂耐药的肿瘤的有效性。
The polo-box domain (PBD) of PLK1 determines mitotic substrate recognition and subcellular localization. Compounds that target PLK1 selectively are required due to the tumor suppressor roles of PLK3. A structure-activity analysis of the PBD phosphopeptide binding motif has identified potent peptides that delineate the determinants required for mimicry by non-peptidic inhibitors and provide insights into the structural basis for the selectivity of inhibitors for the PLK1 PBD. Fragment-ligated inhibitory peptides (FLIPs) obtained through REPLACE have been optimized to enhance in vitro binding and a systematic analysis of selectivity for PLK1 vs 3 has been carried out for peptides and peptidomimetics. Furthermore, these more drug-like non-ATP competitive inhibitors had on target engagement in a cellular context as evidenced by stabilization of PLK1 in a thermal shift assay and by inhibition of the phosphorylation of TCTP, a target of PLK1. Investigation in cells expressing a mutant PLK1 showed that these are sensitive to PBD inhibitors but dramatically resistant to clinically investigated ATP competitive compounds. These results provide further validity of targeting the PBD binding site and progress towards PBD-inhibitors active against tumors resistant to ATP-inhibitors. The polo-box domain (PBD) of PLK1 determines mitotic substrate recognition and localization. Compounds obtained through REPLACE have been optimized to enhance in binding and undertake systematic analysis of selectivity for PLK1 vs PLK3. These more drug-like inhibitors had on target engagement in a cellular thermal shift assay and by inhibition of the phosphorylation of TCTP, a target of PLK1. Results demonstrate further validity of targeting the PBD binding site and progress inhibitors active against tumors resistant to ATP-inhibitors.
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影响因子：
--
作者：
Jiang, Bing-Hua;Liu, Ling-Zhi
通讯作者：
Liu, Ling-Zhi
意外的组氨酸烷基化产生的单开发磷酸肽表现出高的PLK1 Polo-box结构域结合亲和力，并增强了HELA细胞中的抗增殖作用。
影响因子：
2.9
作者：
Qian WJ;Park JE;Lim D;Lai CC;Kelley JA;Park SY;Lee KW;Yaffe MB;Lee KS;Burke TR Jr
通讯作者：
Burke TR Jr
影响因子：
4.8
作者：
Liu, X. Shawn;Song, Bing;Liu, Xiaoqi
通讯作者：
Liu, Xiaoqi
影响因子：
7.3
作者：
Liu, Shu;Premnath, Padmavathy Nandha;McInnes, Campbell
通讯作者：
McInnes, Campbell
影响因子：
4.3
作者：
McKenzie, Lynsey;King, Sharon;Meek, David W.
通讯作者：
Meek, David W.