Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression

  • J Med Chem. 2018 Jan 25;61(2):462-481. doi: 10.1021/acs.jmedchem.6b01816.
Bing Zhou  1 ,  Jiantao Hu  1 ,  Fuming Xu  1 ,  Zhuo Chen  1 ,  Longchuan Bai  1 ,  Ester Fernandez-Salas  1 ,  Mei Lin  1 ,  Liu Liu  1 ,  Chao-Yie Yang  1 ,  Yujun Zhao  1 ,  Donna McEachern  1 ,  Sally Przybranowski  1 ,  Bo Wen  1 ,  Duxin Sun  1 ,  Shaomeng Wang  1
Affiliations
  • 1. University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
PMID: 28339196 DOI: 10.1021/acs.jmedchem.6b01816
Abstract

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.

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