Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs
Angewandte Chemie International Edition
(
IF16.6
)
Pub Date : 2021-10-06, DOI: 10.1002/anie.202108848
Jaeki Min
1
,
Anand Mayasundari
1
,
Fatemeh Keramatnia
1
,
Barbara Jonchere
2
,
Seung Wook Yang
3
,
Jamie Jarusiewicz
1
,
Marisa Actis
1
,
Sourav Das
1
,
Brandon Young
1
,
Jake Slavish
1
,
Lei Yang
1
,
Yong Li
1
,
Xiang Fu
1
,
Shalandus H Garrett
1
,
Mi-Kyung Yun
4
,
Zhenmei Li
4
,
Stanley Nithianantham
1
,
Sergio Chai
1
,
Taosheng Chen
1
,
Anang Shelat
1
,
Richard E Lee
1
,
Gisele Nishiguchi
1
,
Stephen W White
4
,
Martine F Roussel
2
,
Patrick Ryan Potts
3
,
Marcus Fischer
1,
4
,
Zoran Rankovic
1
Affiliation
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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.
中文翻译：
苯基戊二酰亚胺：用于 PROTAC 设计的替代 Cereblon 粘合剂
基于 IMiD 的 PROTAC 在常用的细胞培养基中快速水解，这显着影响其细胞功效。我们设计了基于苯基戊二酰亚胺 (PG) 的新型 BET PROTAC，并表明它们保留了对 CRBN 的亲和力，并表现出改进的化学稳定性。为了证明基于 PG 的 PROTAC 的实用性，我们开发了 SJ995973 ( 4 c )，这是一种独特的有效 BET 蛋白降解剂。
京公网安备 11010802027423号