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Open Access Cysteine-specific Chemical Proteomics: From Target Identification to Drug Discovery

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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.
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Document Type: Research Article

Affiliations: 1: Department of Organic Chemistry NCCR Chemical Biology University of Geneva 30 quai Ernest-Ansermet, Geneva 2: Department of Organic Chemistry NCCR Chemical Biology University of Geneva 30 quai Ernest-Ansermet, Geneva;, Email: [email protected]

Publication date: 01 November 2016

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  • International Journal for Chemistry and Official Membership Journal of the Swiss Chemical Society (SCS) and its Divisions

    CHIMIA, a scientific journal for chemistry in the broadest sense, is published 10 times a year and covers the interests of a wide and diverse readership. Contributions from all fields of chemistry and related areas are considered for publication in the form of Review Articles and Notes. A characteristic feature of CHIMIA are the thematic issues, each devoted to an area of great current significance.

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