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. Epub 2017 Mar 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor / methods
  • Female
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Leukemia / drug therapy
  • Mice, SCID
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteolysis
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • RNA-Binding Proteins / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BRD2 protein, human
  • BRD3 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Indoles
  • Nuclear Proteins
  • Pyrimidines
  • RNA-Binding Proteins
  • Small Molecule Libraries
  • Transcription Factors
  • Protein-Serine-Threonine Kinases