Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.

Autor:	Brennan PJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford; Oxford, UK.; Department of Chemistry & Biochemistry, University of California, Los Angeles; Los Angeles, USA., Saunders RE; GSK, Medicines Research Centre; Stevenage, UK., Spanou M; PerkinElmer; Beaconsfield, UK., Serafini M; Department of Chemistry, Chemistry Research Laboratory, University of Oxford; Oxford, UK., Sun L; Chemical Biology Program, Memorial Sloan Kettering Cancer Center; New York, USA., Heger GP; GSK, Medicines Research Centre; Stevenage, UK., Konopacka A; GSK, Medicines Research Centre; Stevenage, UK., Beveridge RD; Virus Screening Facility, Weatherall Institute of Molecular Medicine, University of Oxford; Oxford, UK., Gordon L; GSK, Medicines Research Centre; Stevenage, UK., Bunally SB; GSK, Medicines Research Centre; Stevenage, UK., Saudemont A; GSK, Medicines Research Centre; Stevenage, UK., Benowitz AB; GSK, Medicines Research Centre; Stevenage, UK., Martinez-Fleites C; GSK, Medicines Research Centre; Stevenage, UK., Queisser MA; GSK, Medicines Research Centre; Stevenage, UK., An H; Chemical Biology Program, Memorial Sloan Kettering Cancer Center; New York, USA., Deane CM; Department of Statistics, University of Oxford; Oxford, UK., Hann MM; GSK, Medicines Research Centre; Stevenage, UK., Brayshaw LL; GSK, Medicines Research Centre; Stevenage, UK., Conway SJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford; Oxford, UK.; Department of Chemistry & Biochemistry, University of California, Los Angeles; Los Angeles, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 16. Date of Electronic Publication: 2024 Mar 16.
DOI:	10.1101/2024.03.15.585309
Abstrakt:	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. Competing Interests: Competing interests: RES, MSp, GPH, AK, LG, SBB, AS, ABB, CMF, MAQ, MMH, and LLB are current or former employees of GSK. PJB, SJC, CMD, MMH, and LLB are inventors on a submitted patent application encompassing the data presented here. MSe, LS, RDB, and HA declare no competing interests.
Databáze:	MEDLINE
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