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Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation.

Titel:	Proteolysis-targeting chimeras with reduced off-targets.
Autor/in / Beteiligte Person:	Nguyen, TM ; Sreekanth, V ; Deb, A ; Kokkonda, P ; Tiwari, PK ; Donovan, KA ; Shoba, V ; Chaudhary, SK ; Mercer, JAM ; Lai, S ; Sadagopan, A ; Jan, M ; Fischer, ES ; Liu, DR ; Ebert, BL ; Choudhary, A
Zeitschrift:	Nature chemistry, Jg. 16 (2024-02-01), Heft 2, S. 218-228
Veröffentlichung:	London : Nature Pub. Group, 2024
Medientyp:	academicJournal
ISSN:	1755-4349 (electronic)
DOI:	10.1038/s41557-023-01379-8
Schlagwort:	Proteolysis Thalidomide pharmacology Ubiquitin-Protein Ligases metabolism Proteins metabolism Thalidomide analogs & derivatives
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nat Chem] 2024 Feb; Vol. 16 (2), pp. 218-228. <i>Date of Electronic Publication: </i>2023 Dec 18. MeSH Terms: Ubiquitin-Protein Ligases* / metabolism ; Proteins* / metabolism ; Thalidomide / *analogs & derivatives ; Proteolysis ; Thalidomide / pharmacology References: Chamberlain, P. P. & Cathers, B. E. Cereblon modulators: low molecular weight inducers of protein degradation. Drug Discov. Today Technol. 31, 29–34 (2019). (PMID: 10.1016/j.ddtec.2019.02.00431200856) ; Kozicka, Z. & Thomä, N. H. Haven’t got a glue: protein surface variation for the design of molecular glue degraders. Cell Chem. Biol. 28, 1032–1047 (2021). (PMID: 10.1016/j.chembiol.2021.04.00933930325) ; Finley, D. Recognition and processing of ubiquitin–protein conjugates by the proteasome. Annu. Rev. Biochem. 78, 477–513 (2009). (PMID: 10.1146/annurev.biochem.78.081507.101607194897273431160) ; Ito, T. et al. 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Proteolysis-targeting chimeras with reduced off-targets.