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发现 2-(3-苯甲酰胺丙氨酰胺基)噻唑-5-羧酸酯类驱动蛋白 HSET（KIFC1）抑制剂和细胞靶标结合探针的开发。

Discovery of 2-(3-Benzamidopropanamido)thiazole-5-carboxylate Inhibitors of the Kinesin HSET (KIFC1) and the Development of Cellular Target Engagement Probes.

机构信息

Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RP, U.K.

Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW7 3RP, U.K.

出版信息

J Med Chem. 2023 Feb 23;66(4):2622-2645. doi: 10.1021/acs.jmedchem.2c01591. Epub 2023 Feb 7.

DOI:10.1021/acs.jmedchem.2c01591
PMID:36749938
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9969401/
Abstract

The existence of multiple centrosomes in some cancer cells can lead to cell death through the formation of multipolar mitotic spindles and consequent aberrant cell division. Many cancer cells rely on HSET (KIFC1) to cluster the extra centrosomes into two groups to mimic the bipolar spindle formation of non-centrosome-amplified cells and ensure their survival. Here, we report the discovery of a novel 2-(3-benzamidopropanamido)thiazole-5-carboxylate with micromolar in vitro inhibition of HSET (KIFC1) through high-throughput screening and its progression to ATP-competitive compounds with nanomolar biochemical potency and high selectivity against the opposing mitotic kinesin Eg5. Induction of the multipolar phenotype was shown in centrosome-amplified human cancer cells treated with these inhibitors. In addition, a suitable linker position was identified to allow the synthesis of both fluorescent- and -cyclooctene (TCO)-tagged probes, which demonstrated direct compound binding to the HSET protein and confirmed target engagement in cells, through a click-chemistry approach.

摘要

在一些癌细胞中存在多个中心体，这可能导致细胞死亡，形成多极有丝分裂纺锤体，并导致异常的细胞分裂。许多癌细胞依赖 HSET（KIFC1）将额外的中心体聚类成两组，以模拟非中心体扩增细胞的双极纺锤体形成，并确保其存活。在这里，我们报告了一种新型 2-(3-苯甲酰胺丙基酰胺基)噻唑-5-羧酸的发现，该化合物通过高通量筛选对 HSET（KIFC1）具有微摩尔体外抑制作用，并通过 ATP 竞争性化合物进展为具有纳摩尔生化效力和针对相反的有丝分裂运动蛋白 Eg5 的高选择性的化合物。在用这些抑制剂处理中心体扩增的人类癌细胞中显示出多极表型的诱导。此外，确定了合适的连接子位置，以允许合成荧光标记和环辛烯（TCO）标记的探针，通过点击化学方法证明了直接化合物与 HSET 蛋白的结合，并证实了细胞中的靶标结合。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/0d74bb1be59b/jm2c01591_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/8c5aeba43e4f/jm2c01591_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/cfa4e35f863d/jm2c01591_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/313c56cc9c3e/jm2c01591_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/64ba3baeab48/jm2c01591_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/5fb0a70fd309/jm2c01591_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/8800dfc5b076/jm2c01591_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/1be58ea2774d/jm2c01591_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/3b4f86dddfe3/jm2c01591_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/0d74bb1be59b/jm2c01591_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/8c5aeba43e4f/jm2c01591_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/cfa4e35f863d/jm2c01591_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/313c56cc9c3e/jm2c01591_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/64ba3baeab48/jm2c01591_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/5fb0a70fd309/jm2c01591_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/8800dfc5b076/jm2c01591_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/1be58ea2774d/jm2c01591_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/3b4f86dddfe3/jm2c01591_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/815d/9969401/0d74bb1be59b/jm2c01591_0009.jpg

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