Cysteine-specific Chemical Proteomics: From Target Identification to Drug Discovery
Cysteine-specific Chemical Proteomics: From Target Identification to Drug Discovery
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DOI：
10.2533/chimia.2016.764
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发表时间：
2016-01-01
期刊：
影响因子：
1.2
通讯作者：
Adibekian, Alexander
中科院分区：
文献类型：
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作者：
Hoch, Dominic G.;Abegg, Daniel;Adibekian, Alexander
我们的实验室专注于化学蛋白质组学，发现新的半胱氨酸反应性小分子，具有有趣的生物医学活性，以及鉴定和详细表征其蛋白质组学靶点。在这篇综述文章中，我们总结了自2013年以来我们在这一研究领域的进展。我们开发了一种新的基于质谱的化学蛋白质组学方法，可以检测和监测任何细胞蛋白质组中多达3000个反应性半胱氨酸。这是通过战略性地使用两种可点击的半胱氨酸反应性化学探针来实现的，所述化学探针具有互补的底物选择性特征，碘乙酰胺和乙炔基苯碘多索酮。使用这种方法，我们已经能够确定姜黄素的直接生物靶点，姜黄素是一种具有抗癌活性的二芳基庚烷类天然产物，而脱氧地胆色素是一种具有高度细胞毒性的天然倍半萜内酯。此外，我们已经开发了氯甲基三唑（CMT）作为半胱氨酸反应性抑制剂的新型化学支架，可以从市售底物中仅通过两个化学步骤获得。从一小批氯甲基三唑中，我们发现化合物AA-CW 236是MGMT的第一个非假底物抑制剂，MGMT是一种DNA修复蛋白，可使几种毁灭性的癌症形式对化疗产生耐药性。
Our laboratory focuses on chemical proteomics-enabled discovery of new cysteine-reactive small molecules with intriguing biomedical activities as well as identification and detailed characterization of their proteomic targets. In this overview article, we summarize our progress since 2013 in this research field. We have developed a novel mass spectrometry-based chemoproteomic method that allows detection and monitoring of up to 3000 reactive cysteines in any cellular proteome. This is achieved via strategic use of two clickable, cysteine-reactive chemical probes with complementary substrate selectivity profiles, iodoacetamide and ethynyl benziodoxolone. Using this method, we have been able to identify the direct biological targets of curcumin, a diarylheptanoid natural product with anticancer activity, and deoxyelephantopin, a highly cytotoxic natural sesquiterpene lactone. Furthermore, we have developed chloromethyl triazoles (CMTs) as a novel chemical scaffold for cysteine-reactive inhibitors that can be accessed from commercially available substrates in only two chemical steps. From a small collection of chloromethyl triazoles, we have identified compound AA-CW236 as the first non-pseudosubstrate inhibitor of MGMT, a DNA repair protein that renders several devastating cancer forms resistant to chemotherapy.