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HaloTag-targeted Sirtuin-rearranging Ligand (SirReal) for the Development of Proteolysis-targeting Chimeras (PROTACs) Against the Lysine Deacetylase Sirtuin 2 (Sirt2)
Abstract: We have discovered the sirtuin-rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+-dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so-called proteolysis-targeting chimera (PROTAC) enabled small-molecule-induced degradation of Sirt2. Herein, we report the structure-based development of a chloroalkylated SirReal that induces the degradation of Sirt2 mediated by Halo-tagged E3 ubiquitin ligases. Using this orthogonal approach for Sirt2 degradation, we show that other E3 ligases than cereblon, such as the E3 ubiquitin ligase parkin, can also be harnessed for small-molecule-induced Sirt2 degradation, thereby emphasizing the great potential of parkin to be used as an E3 ligase for new PROTACs approaches. Thus, our study provides new insights into targeted protein degradation in general and Sirt2 degradation in particular
Wittgenstein's Vienna
This is a remarkable book about a man (perhaps the most important and original philosopher of our age), a society (the corrupt Austro-Hungarian Empire on the eve of dissolution), and a city (Vienna, with its fin-de siècle gaiety and corrosive melancholy). The central figure in this study of a crumbling society that gave birth to the modern world is Wittgenstein, the brilliant and gifted young thinker. With others, including Freud, Viktor Adler, and Arnold Schoenberg, he forged his ideas in a classical revolt against the stuffy, doomed, and moralistic lives of the old regime. As a portrait of Wittgenstein, the book is superbly realized; it is even better as a portrait of the age, with dazzling and unusual parallels to our own confused society. “Allan Janik and Stephen Toulmin have acted on a striking premise: an understanding of prewar Vienna, Wittgenstein's native city, will make it easier to comprehend both his work and our own problems....This is an independent work containing much that is challenging, new, and useful.”—New York Times Book Review.
Chemical Epigenetics
This book presents an authoritative review of the most significant findings about all the epigenetic targets (writers, readers, and erasers) and their implication in physiology and pathology. The book also covers the design, synthesis and biological validation of epigenetic chemical modulators, which can be useful as novel chemotherapeutic agents. Particular attention is given to the chemical mechanisms of action of these molecules and to the drug discovery prose which allows their identification. This book will appeal to students who want to know the extensive progresses made by epigenetics (targets and modulators) in the last years from the beginning, and to specialized scientists who need an instrument to quickly search and check historical and/or updated notices about epigenetics.
House documents
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Annual Report
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