Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Bing ZhouJiantao HuFuming XuZhuo ChenLongchuan BaiEster Fernandez-SalasMei LinLiu LiuChao-Yie YangYujun ZhaoDonna McEachernSally PrzybranowskiBo WenDuxin SunShaomeng WangPublished in: Journal of medicinal chemistry (2017)
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.
Keyphrases
- small molecule
- protein protein
- air pollution
- gene expression
- dna methylation
- heavy metals
- transcription factor
- bone marrow
- acute myeloid leukemia
- polycyclic aromatic hydrocarbons
- copy number
- artificial intelligence
- big data
- young adults
- squamous cell
- electronic health record
- amino acid
- single cell
- deep learning
- sensitive detection
- lymph node metastasis
- data analysis