Confounding Factors in Targeted Degradation of Short-Lived Proteins

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 modelin...

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Published in:ACS chemical biology 2024-07, Vol.19 (7), p.1484-1494
Main Authors: Vetma, Vesna, Perez, Laura Casares, Eliaš, Ján, Stingu, Andrea, Kombara, Anju, Gmaschitz, Teresa, Braun, Nina, Ciftci, Tuncay, Dahmann, Georg, Diers, Emelyne, Gerstberger, Thomas, Greb, Peter, Kidd, Giorgia, Kofink, Christiane, Puoti, Ilaria, Spiteri, Valentina, Trainor, Nicole, Weinstabl, Harald, Westermaier, Yvonne, Whitworth, Claire, Ciulli, Alessio, Farnaby, William, McAulay, Kirsten, Frost, Aileen B., Chessum, Nicola, Koegl, Manfred
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container_end_page 1494
container_issue 7
container_start_page 1484
container_title ACS chemical biology
container_volume 19
creator Vetma, Vesna
Perez, Laura Casares
Eliaš, Ján
Stingu, Andrea
Kombara, Anju
Gmaschitz, Teresa
Braun, Nina
Ciftci, Tuncay
Dahmann, Georg
Diers, Emelyne
Gerstberger, Thomas
Greb, Peter
Kidd, Giorgia
Kofink, Christiane
Puoti, Ilaria
Spiteri, Valentina
Trainor, Nicole
Weinstabl, Harald
Westermaier, Yvonne
Whitworth, Claire
Ciulli, Alessio
Farnaby, William
McAulay, Kirsten
Frost, Aileen B.
Chessum, Nicola
Koegl, Manfred
description 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.
doi_str_mv 10.1021/acschembio.4c00152
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title Confounding Factors in Targeted Degradation of Short-Lived Proteins
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