Activity-based proteome profiling of potential cellular targets of Orlistat - an FDA-approved drug with anti-tumor activities

Yang, Peng-Yu, Liu, Kai, Ngai, Mun Hong , Lear, Martin J., Wenk, Markus R. and Yao, Shao Q. (2010) Activity-based proteome profiling of potential cellular targets of Orlistat - an FDA-approved drug with anti-tumor activities. Journal of the American Chemical Society, 132 (2). pp. 656-666. ISSN 0002-7863

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Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural product like, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.

Keywords:Total synthesis, Chemical proteomics, Orlistat, Anti-tumor activities, Drug off-targets
Subjects:F Physical Sciences > F165 Biomolecular Chemistry
F Physical Sciences > F160 Organic Chemistry
C Biological Sciences > C720 Biological Chemistry
F Physical Sciences > F163 Bio-organic Chemistry
Divisions:College of Science > School of Chemistry
ID Code:17110
Deposited On:16 Apr 2015 14:40

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