Discovery of a
Small-Molecule Degrader of Bromodomain
and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies
and Capable of Achieving Tumor Regression
Version 2 2017-03-25, 16:43
Version 1 2017-03-24, 20:03
Posted on 2017-03-25 - 16:43
The
bromodomain and extra-terminal (BET) family proteins, consisting
of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic
“readers” and play a key role in the regulation of gene
transcription. BET proteins are considered to be attractive therapeutic
targets for cancer and other human diseases. Recently, heterobifunctional
small-molecule BET degraders have been designed based upon the proteolysis
targeting chimera (PROTAC) concept to induce BET protein degradation.
Herein, we present our design, synthesis, and evaluation of a new
class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as
low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces
rapid tumor regression in vivo against RS4;11 xenograft tumors. These
data establish that compound 23 (BETd-260/ZBC260) is
a highly potent and efficacious BET
degrader.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Zhou, Bing; Hu, Jiantao; Xu, Fuming; Chen, Zhuo; Bai, Longchuan; Fernandez-Salas, Ester; et al. (2017). Discovery of a
Small-Molecule Degrader of Bromodomain
and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies
and Capable of Achieving Tumor Regression. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.6b01816
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
AUTHORS (15)
BZ
Bing Zhou
JH
Jiantao Hu
FX
Fuming Xu
ZC
Zhuo Chen
LB
Longchuan Bai
EF
Ester Fernandez-Salas
ML
Mei Lin
LL
Liu Liu
CY
Chao-Yie Yang
YZ
Yujun Zhao
DM
Donna McEachern
SP
Sally Przybranowski
BW
Bo Wen
DS
Duxin Sun
SW
Shaomeng Wang
KEYWORDS
RSBET degraderTumor Regressionheterobifunctional small-molecule BET degradersPicomolar Cellular Potenciestumor regressiongene transcriptionBET protein degradationbet proteinsdegrades BRD 4 proteinSmall-Molecule Degrader51 pMtestis-specific BRDT memberscompound 23family proteinsPROTAC BET degradersIC 50 value30 pM