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用于测量活细胞中PLK1靶点结合情况的细胞渗透性纳米BRET探针的研发。

Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells.

作者信息

Yang Xuan, Smith Jeffery L, Beck Michael T, Wilkinson Jennifer M, Michaud Ani, Vasta James D, Robers Matthew B, Willson Timothy M

机构信息

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711, USA.

出版信息

bioRxiv. 2023 Mar 7:2023.02.25.529946. doi: 10.1101/2023.02.25.529946.

DOI:10.1101/2023.02.25.529946
PMID:36865333
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9980182/
Abstract

PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential anti target of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1 we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe 11 was used to configure NanoBRET target engagement assays for PLK1, PLK2, and PLK3 and measure the potency of several known PLK inhibitors. In cell target engagement for PLK1 was in good agreement with the reported cellular potency for inhibition of cell proliferation. Probe 11 enabled investigation of the promiscuity of adavosertib, which had been described as a dual PLK1/WEE1 inhibitor in biochemical assays. Live cell target engagement analysis of adavosertib by NanoBRET demonstrated PLK activity at micromolar concentrations but only selective engagement of WEE1 at clinically relevant doses.

摘要

PLK1是一种调节有丝分裂的蛋白激酶，既是重要的肿瘤学药物靶点，也是DNA损伤反应途径药物或抗感染宿主激酶的潜在抗靶点。为了将活细胞纳米BRET靶点结合分析的范围扩展到包括PLK1，我们基于在几种选择性PLK抑制剂中发现的苯胺基四氢蝶啶化学类型开发了一种能量转移探针。探针11用于配置针对PLK1、PLK2和PLK3的纳米BRET靶点结合分析，并测量几种已知PLK抑制剂的效力。在细胞中，PLK1的靶点结合与报道的抑制细胞增殖的细胞效力高度一致。探针11能够研究阿多福韦酯的选择性，在生化分析中阿多福韦酯被描述为一种双PLK1/WEE1抑制剂。通过纳米BRET对阿多福韦酯进行活细胞靶点结合分析表明，在微摩尔浓度下存在PLK活性，但在临床相关剂量下仅对WEE1有选择性结合。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/47bdbdd20bcf/nihpp-2023.02.25.529946v3-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/a5ae754f70c7/nihpp-2023.02.25.529946v3-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/5aac3088075c/nihpp-2023.02.25.529946v3-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/406ab0da4940/nihpp-2023.02.25.529946v3-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/47bdbdd20bcf/nihpp-2023.02.25.529946v3-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/a5ae754f70c7/nihpp-2023.02.25.529946v3-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/5aac3088075c/nihpp-2023.02.25.529946v3-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/406ab0da4940/nihpp-2023.02.25.529946v3-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b03/9994545/47bdbdd20bcf/nihpp-2023.02.25.529946v3-f0005.jpg

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Present and Future Perspective on PLK1 Inhibition in Cancer Treatment.癌症治疗中PLK1抑制的现状与未来展望。
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