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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Published in:Angewandte Chemie International Edition Vol. 60; no. 51; pp. 26663 - 26670
Main Authors: 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
Format: Journal Article
Language:English
Published: WEINHEIM Wiley 13.12.2021
Wiley Subscription Services, Inc
Wiley-VCH Verlag
Edition:International ed. in English
Subjects:
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
Online Access:Get full text
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Summary: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.
Bibliography:These authors contributed equally to this work.
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PMCID: PMC8648984
ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.202108848