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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Abstract 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.
AbstractList 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.
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.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.
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 (IC =3 pM; BRD4 DC =0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed 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 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 4c (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 (4c), a uniquely potent degrader of BET proteins.
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 (IC 50 =3 pM; BRD4 DC 50 =0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN‐directed 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 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.
Author Chai, Sergio
Keramatnia, Fatemeh
Li, Yong
Potts, Patrick Ryan
Shelat, Anang
Nithianantham, Stanley
Li, Zhenmei
Chen, Taosheng
Rankovic, Zoran
Young, Brandon
Yang, Seung Wook
Slavish, Jake
Yun, Mi‐Kyung
Jonchere, Barbara
White, Stephen W.
Garrett, Shalandus H.
Roussel, Martine F.
Actis, Marisa
Mayasundari, Anand
Fu, Xiang
Min, Jaeki
Lee, Richard E.
Yang, Lei
Fischer, Marcus
Das, Sourav
Jarusiewicz, Jamie
Nishiguchi, Gisele
AuthorAffiliation d Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
c Department of Cell & Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
a Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
b Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/34614283$$D View this record in MEDLINE/PubMed
https://u-picardie.hal.science/hal-03720142$$DView record in HAL
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Copyright 2021 Wiley‐VCH GmbH
2021 Wiley-VCH GmbH.
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Issue 51
Keywords 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
Language English
License 2021 Wiley-VCH GmbH.
Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0
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Notes These authors contributed equally to this work.
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Snippet Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis‐targeting chimera (PROTAC) approaches, owing to favorable drug‐like...
Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like...
Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like...
Source Web of Science
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hal
proquest
pubmed
webofscience
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wiley
SourceType Open Access Repository
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StartPage 26663
SubjectTerms 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
Title Phenyl‐Glutarimides: Alternative Cereblon Binders for the Design of PROTACs
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fanie.202108848
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https://www.ncbi.nlm.nih.gov/pubmed/34614283
https://www.proquest.com/docview/2606919595
https://www.proquest.com/docview/2580014787
https://u-picardie.hal.science/hal-03720142
https://pubmed.ncbi.nlm.nih.gov/PMC8648984
Volume 60
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