Phenyl‐Glutarimides: Alternative Cereblon Binders for the Design of PROTACs

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis‐targeting chimera (PROTAC) approaches, owing to favorable drug‐like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolys...

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Vydáno v:	Angewandte Chemie International Edition Ročník 60; číslo 51; s. 26663 - 26670
Hlavní autoři:	Min, Jaeki, Mayasundari, Anand, Keramatnia, Fatemeh, Jonchere, Barbara, Yang, Seung Wook, Jarusiewicz, Jamie, Actis, Marisa, Das, Sourav, Young, Brandon, Slavish, Jake, Yang, Lei, Li, Yong, Fu, Xiang, Garrett, Shalandus H., Yun, Mi‐Kyung, Li, Zhenmei, Nithianantham, Stanley, Chai, Sergio, Chen, Taosheng, Shelat, Anang, Lee, Richard E., Nishiguchi, Gisele, White, Stephen W., Roussel, Martine F., Potts, Patrick Ryan, Fischer, Marcus, Rankovic, Zoran
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	WEINHEIM Wiley 13.12.2021 Wiley Subscription Services, Inc Wiley-VCH Verlag
Vydání:	International ed. in English
Témata:	Acute myeloid leukemia Adaptor Proteins, Signal Transducing - chemistry Binders Body fluids cereblon Chemistry Chemistry, Multidisciplinary Human health and pathology Humans Hydrolysis IMiD Immunomodulation Leukemia Life Sciences Ligands Myeloid leukemia phenyl glutarimide Physical Sciences Piperidones - chemistry PROTAC Proteolysis Science & Technology Ubiquitin-Protein Ligases - chemistry CC-90009 phenyl glutarimide COMPLEX PROTAC UBIQUITIN LIGASE HYDROLYSIS THALIDOMIDE GSPT1 cereblon METABOLISM DEGRADER PG E3 LIGASE MODULATOR TARGETED PROTEIN-DEGRADATION IMiD Ubiquitin-Protein Ligases Hydrolysis Signal Transducing Proteolysis Humans Piperidones Adaptor Proteins
ISSN:	1433-7851, 1521-3773, 1521-3773
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Popis
Shrnutí:	Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis‐targeting chimera (PROTAC) approaches, owing to favorable drug‐like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD‐based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4 c (SJ995973), a uniquely potent degrader of bromodomain and extra‐terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4‐11 cells at low picomolar concentrations (IC50=3 pM; BRD4 DC50=0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN‐directed PROTACs. IMiD‐based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel BET PROTACs based on phenyl glutarimide (PG) and showed that they retained affinity for CRBN and displayed improved chemical stability. To demonstrate the utility of PG‐based PROTACs we developed SJ995973 (4 c), a uniquely potent degrader of BET proteins.
Bibliografie:	These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC8648984
ISSN:	1433-7851 1521-3773 1521-3773
DOI:	10.1002/anie.202108848