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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
Azologization and Repurposing of a Hetero-stilbene-based Kinase Inhibitor: Towards the Design of Photoswitchable Sirtuin Inhibitors
Abstract: The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue. By this intramolecular azologization, the shape of the molecule was left unaltered, whereas the photoswitching ability was improved. As anticipated, the highly analogous compound showed similar activity in its thermodynamically stable stretched-out (E)-form. Irradiation of this isomer triggers isomerisation to the long-lived (Z)-configuration with a bent geometry causing a considerably shorter end-to-end distance. The resulting affinity shifts are intended to enable real-time photomodulation of sirtuins in vitro
A Poetic Plunge
These poems take you on a dive into the creative journey of a professional dancer and all the experiences and people that got her there along the way. It is a biography in poetic form.
Natalie Portman
Natalie Portman is only 20 years old, but already she has co-starred in nine films with everyone from Woody Allen to Al Pacino and is considered the best young actress in Hollywood. In the first biography of this dynamic star, Dickerson examines the charm and wit of her professional persona, while revealing the emotional life of the real Portman. From her relationship with her parents, her long friendship with Britney Spears, her life at Harvard, and her involvement in Star Wars, this book delves into a story never before told. Illustrated with 8 colour and 15 b/w photos.
Natalie: A Memoir About Natalie Wood by Her Sister
This New York Times bestseller is the most intimate possible remembrance of Natalie Wood's tempestuous life and tragic death. A book that only Natalie Wood's sister could have written - a warm but unflinchingly candid account of a great star's passionate love affairs, violent fights, stormy marriages, bitter divorces, and of her controversial death by drowning at the age of forty-three, stunning a nation that adored her. Now includes rare family photographs.
Natalie Wood: A Biography
ABOUT THE BOOK Who is Natalie Wood? On Sunday, November 29, 1981, the world woke to the news that the talented and well-loved movie star Natalie Wood was dead. She was only 43 years old. But as details of her death became known, the loss became both a tragedy and a mystery. How was it possible that she would die from the one thing that terrified her most: drowning in dark water? For many, it was inconceivable unless something more sinister occurred. Officially, the cause of death was an accident. Although the specifics are unknown, speculation by the authorities and by Robert Wagner, her husband who was on the boat with her at the time, is that she attempted to retie the dinghy that was thum...
Natalie
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Natasha
The explosive, bestselling biography of Natalie Wood is now in paperback, hailed as "a poignant, intensely sympathetic portrait" ("Los Angeles Times"). A two-night mini-series is scheduled in May 2002 on ABC. Two 8-page photo inserts. Copyright © Libri GmbH. All rights reserved.
Natalie Wood
In this riveting new biography of Natalie Wood, Lambert gives readers the most candid, illuminating book yet about this sparkling, generous, fragile actress whose life embodied Hollywood. 65 photos.
