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Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells.白花丹内酯共价靶向并抑制乳腺癌细胞中的粘着斑激酶。
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Curr Opin Chem Biol. 2019 Jun;50:29-36. doi: 10.1016/j.cbpa.2019.02.010. Epub 2019 Mar 18.
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Lysine-Targeted Inhibitors and Chemoproteomic Probes.赖氨酸靶向抑制剂和化学蛋白质组探针。
Annu Rev Biochem. 2019 Jun 20;88:365-381. doi: 10.1146/annurev-biochem-061516-044805. Epub 2019 Jan 11.
5
Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.新兴与重现的靶向共价抑制剂弹头：在药物化学和化学生物学中的应用。
J Med Chem. 2019 Jun 27;62(12):5673-5724. doi: 10.1021/acs.jmedchem.8b01153. Epub 2019 Jan 25.
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DeltaMass: Automated Detection and Visualization of Mass Shifts in Proteomic Open-Search Results.DeltaMass：蛋白质组学开放式检索结果中质量漂移的自动检测和可视化。
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A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification.一种用于直接和蛋白质组范围共价抑制剂靶位鉴定的化学蛋白质组学策略。
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8
A road map for prioritizing warheads for cysteine targeting covalent inhibitors.为半胱氨酸靶向共价抑制剂确定弹头优先级的路线图。
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9
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α-亚甲基-β-内酰胺支架用于开发选择性谱两端的化学探针。

α-Methylene-β-Lactone Scaffold for Developing Chemical Probes at the Two Ends of the Selectivity Spectrum.

机构信息

Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA.

Chemical Biology & Proteomics, Biogen, Cambridge, MA 02142, USA.

出版信息

Chembiochem. 2021 Feb 2;22(3):505-515. doi: 10.1002/cbic.202000605. Epub 2020 Nov 11.

DOI:10.1002/cbic.202000605
PMID:32964640
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8114233/
Abstract

The utilities of an α-methylene-β-lactone (MeLac) moiety as a warhead composed of multiple electrophilic sites are reported. We demonstrate that a MeLac-alkyne not only reacts with diverse proteins as a broadly reactive measurement probe, but also recruits reduced endogenous glutathione (GSH) to assemble a selective chemical probe of GSH-β-lactone (GSH-Lac)-alkyne in live cells. Tandem mass spectrometry reveals that MeLac reacts with nucleophilic cysteine, serine, lysine, threonine, and tyrosine residues, through either Michael or acyl addition. A peptide-centric proteomics platform demonstrates that the proteomic selectivity profiles of orlistat and parthenolide, which have distinct reactivities, are measurable by MeLac-alkyne as a high-coverage probe. The GSH-Lac-alkyne selectively probes the glutathione S-transferase P responsible for multidrug resistance. The assembly of the GSH-Lac probe exemplifies a modular and scalable route to develop selective probes with different recognizing moieties.

摘要

报道了作为由多个亲电位点组成的弹头的α-亚甲基-β-内酰胺 (MeLac) 部分的用途。我们证明，MeLac-炔不仅可以作为广泛反应性的测量探针与各种蛋白质反应，而且还可以募集还原内源性谷胱甘肽 (GSH)，以在活细胞中组装选择性的 GSH-β-内酰胺 (GSH-Lac)-炔探针。串联质谱揭示，MeLac 通过迈克尔加成或酰基加成与亲核半胱氨酸、丝氨酸、赖氨酸、苏氨酸和酪氨酸残基反应。基于肽的蛋白质组学平台表明，奥利斯他和小白菊内酯的蛋白质组选择性特征，具有不同的反应性，可用 MeLac-炔作为高覆盖率探针进行测量。GSH-Lac-炔选择性地探测负责多药耐药的谷胱甘肽 S-转移酶 P。GSH-Lac 探针的组装体现了一种模块化和可扩展的方法，可用于开发具有不同识别部分的选择性探针。