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Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.
ChemMedChem ( IF 3.4 ) Pub Date : 2020-03-30 , DOI: 10.1002/cmdc.202000137
Merissa Baxter 1, 2 , Danda Chapagai 1 , Sandra Craig 1, 3 , Cecilia Hurtado 1, 4 , Jessy Varghese 1 , Elmar Nurmemmedov 5 , Michael D Wyatt 1 , Campbell McInnes 1
Affiliation  

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 nonpeptidic 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 PLK3 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 cells are sensitive to PBD inhibitors but dramatically resistant to clinically investigated ATP‐competitive compounds. These results further validate targeting the PBD binding site in the move towards PLK1 inhibitors that are active against tumors resistant to ATP inhibitors.

中文翻译:

肽模拟 Polo-Box 靶向抑制剂,可与肿瘤细胞中的 PLK1 结合,并对 PLK3 肿瘤抑制因子具有选择性。

PLK1 的 polo-box 结构域 (PBD) 决定有丝分裂底物识别和亚细胞定位。由于 PLK3 的肿瘤抑制作用,需要选择性靶向 PLK1 的化合物。PBD 磷酸肽结合基序的结构活性分析已鉴定出有效的肽,这些肽描述了非肽抑制剂模拟所需的决定因素,并为 PLK1 PBD 抑制剂的选择性的结构基础提供了见解。通过 REPLACE 获得的片段连接抑制肽 (FLIP) 已经过优化,可增强体外结合,并且已对肽和肽模拟物的 PLK1 与 PLK3 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作用,热位移测定中 PLK1 的稳定性以及 PLK1 靶标 TCTP 磷酸化的抑制证明了这一点。对表达突变型 PLK1 的细胞的研究表明,这些细胞对 PBD 抑制剂敏感,但对临床研究的 ATP 竞争性化合物具有显着耐药性。这些结果进一步验证了以 PBD 结合位点为目标的 PLK1 抑制剂的发展,这些抑制剂对 ATP 抑制剂具有抗性的肿瘤具有活性。
更新日期:2020-03-30
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