Open AccessDiscovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression
Author(s) -
Bing Zhou,
Jiantao Hu,
Fuming Xu,
Zhuo Chen,
Longchuan Bai,
Ester FernándezSalas,
Mei Lin,
Liu Liu,
Chao Yang,
Yujun Zhao,
Donna McEachern,
Sally Przybranowski,
Bo Wen,
Duxin Sun,
Shaomeng Wang
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.6b01816
Subject(s) - bromodomain , brd4 , chemistry , bet inhibitor , epigenetics , small molecule , proteolysis , fusion protein , cancer research , biochemistry , microbiology and biotechnology , computational biology , gene , biology , enzyme , recombinant dna
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 IC 50 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.