Vesna Vetma, Laura Casares Perez, Ján Eliaš, Andrea Stingu, Anju Kombara, Teresa Gmaschitz, Nina Braun, Tuncay Ciftci, Georg Dahmann, Emelyne Diers, Thomas Gerstberger, Peter Greb, Giorgia Kidd, Christiane Kofink, Ilaria Puoti, Valentina Spiteri, Nicole Trainor, Harald Weinstabl, Yvonne Westermaier, Claire Whitworth, Alessio Ciulli, William Farnaby, Kirsten McAulay, Aileen B. Frost, Nicola Chessum and Manfred Koegl*,
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引用次数: 0
Abstract
Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but to what extent it influences target protein degradation has not been systematically explored. Using simple mathematical modeling of protein degradation, we find that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a degrader agent which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein-degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required to conclude that a novel agent works as a bona fide targeted protein degrader.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.