Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells

Brennan, P. J.; Saunders, R. E.; Spanou, M.; Serafini, M.; Sun, L.; Heger, G. P.; Konopacka, A.; Beveridge, R. D.; Gordon, L.; Bunally, S. B.; Saudemont, A.; Benowitz, A. B.; Martinez-Fleites, C.; Queisser, M. A.; An, H.; Deane, C. M.; Hann, M. M.; Brayshaw, L. L.; Conway, S. J.

doi:10.1101/2024.03.15.585309

bioRxiv · 10.1101/2024.03.15.585309

Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells

Brennan, P. J.·Saunders, R. E.·Spanou, M.·Serafini, M.·Sun, L.·Heger, G. P.·Konopacka, A.·Beveridge, R. D.·Gordon, L.·Bunally, S. B.·Saudemont, A.·Benowitz, A. B.·Martinez-Fleites, C.·Queisser, M. A.·An, H.·Deane, C. M.·Hann, M. M.·Brayshaw, L. L.·Conway, S. J.

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Abstract

Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3. In proof-of-concept studies, this system was applied to induce efficient degradation of TRIM28, a disease-relevant protein with no known small molecule binders. We anticipate that this system will make a valuable addition to the current arsenal of degron systems for use in target validation. One-Sentence SummaryEngineered zinc-finger-based degrons enable targeted protein degradation induced by selective molecular glues.

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Brennan, P. J., Saunders, R. E., Spanou, M., Serafini, M., Sun, L., Heger, G. P., Konopacka, A., Beveridge, R. D., Gordon, L., Bunally, S. B., Saudemont, A., Benowitz, A. B., Martinez-Fleites, C., Queisser, M. A., An, H., Deane, C. M., Hann, M. M., Brayshaw, L. L., Conway, S. J.. 2024-03-16. Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells. https://doi.org/10.1101/2024.03.15.585309

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