Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3

Proc Natl Acad Sci U S A. 2016 May 3;113(18):4970-5. doi: 10.1073/pnas.1604274113. Epub 2016 Apr 15.


Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.

Keywords: breast cancer; drug development; protein–protein interactions; small-molecule inhibitor; steroid receptor coactivator.

Publication types

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

MeSH terms

  • Animals
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Hydrazones / pharmacokinetics
  • Hydrazones / pharmacology*
  • Mice
  • Nuclear Receptor Coactivator 3 / antagonists & inhibitors*
  • Nuclear Receptor Coactivator 3 / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Transcription, Genetic / drug effects


  • Benzimidazoles
  • Hydrazones
  • Nuclear Receptor Coactivator 3