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小分子荧光配体用于趋化因子受体 CXCR4。

Small-Molecule Fluorescent Ligands for the CXCR4 Chemokine Receptor.

机构信息

Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.

Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands NG7 2UH, U.K.

出版信息

J Med Chem. 2023 Apr 13;66(7):5208-5222. doi: 10.1021/acs.jmedchem.3c00151. Epub 2023 Mar 21.

DOI:10.1021/acs.jmedchem.3c00151
PMID:36944083
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10108349/
Abstract

The C-X-C chemokine receptor type 4, or CXCR4, is a chemokine receptor found to promote cancer progression and metastasis of various cancer cell types. To investigate the pharmacology of this receptor, and to further elucidate its role in cancer, novel chemical tools are a necessity. In the present study, using classic medicinal chemistry approaches, small-molecule-based fluorescent probes were designed and synthesized based on previously reported small-molecule antagonists. Here, we report the development of three distinct chemical classes of fluorescent probes that show specific binding to the CXCR4 receptor in a novel fluorescence-based NanoBRET binding assay (p ranging 6.6-7.1). Due to their retained affinity at CXCR4, we furthermore report their use in competition binding experiments and confocal microscopy to investigate the pharmacology and cellular distribution of this receptor.

摘要

C-X-C 趋化因子受体 4（C-X-C chemokine receptor type 4，或 CXCR4）是一种趋化因子受体，被发现可促进多种癌症细胞类型的癌症进展和转移。为了研究该受体的药理学，并进一步阐明其在癌症中的作用，需要新型化学工具。在本研究中，我们使用经典的药物化学方法，基于先前报道的小分子拮抗剂设计并合成了基于小分子的荧光探针。在此，我们报告了三种不同化学类别的荧光探针的开发，这些探针在新型基于荧光的 NanoBRET 结合测定法（p 值为 6.6-7.1）中显示出与 CXCR4 受体的特异性结合。由于它们在 CXCR4 上保持亲和力，我们还报告了它们在竞争结合实验和共聚焦显微镜中的使用，以研究该受体的药理学和细胞分布。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f5b03e346d4f/jm3c00151_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/bccf8f02e1ca/jm3c00151_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/81d58cc8f847/jm3c00151_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/3228189126a6/jm3c00151_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f412e390a73e/jm3c00151_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/b6e064337255/jm3c00151_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/7564d729cf8e/jm3c00151_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/012d0bbddf57/jm3c00151_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f3d3e96c884c/jm3c00151_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/bc5f27afe451/jm3c00151_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f5b03e346d4f/jm3c00151_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/bccf8f02e1ca/jm3c00151_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/81d58cc8f847/jm3c00151_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/3228189126a6/jm3c00151_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f412e390a73e/jm3c00151_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/b6e064337255/jm3c00151_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/7564d729cf8e/jm3c00151_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/012d0bbddf57/jm3c00151_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f3d3e96c884c/jm3c00151_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/bc5f27afe451/jm3c00151_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a398/10108349/f5b03e346d4f/jm3c00151_0008.jpg

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