Confounding Factors in Targeted Degradation of Short-Lived Proteins

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 WhitworthAlessio Ciulli, William Farnaby, Kirsten McAulay, Aileen B. Frost, Nicola Chessum, Manfred Koegl (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Number of pages11
JournalACS Chemical Biology
Early online date3 Jul 2024
DOIs
Publication statusE-pub ahead of print - 3 Jul 2024

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