Patrick J Brennan, Rebecca E Saunders, Mary Spanou, Marta Serafini, Liang Sun, Guillaume P Heger, Agnieszka Konopacka, Ryan D Beveridge, Laurie Gordon, Shenaz B Bunally, Aurore Saudemont, Andrew B Benowitz, Carlos Martinez-Fleites, Markus A Queisser, Heeseon An, Charlotte M Deane, Michael M Hann, Lewis L Brayshaw, Stuart J Conway
UNLABELLED: 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...
March 16, 2024: bioRxiv