Drugging the undruggable steroid receptor coactivators

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 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 IC 50 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. Support or Funding Information This work is supported in part by National Institutes of Health Grants R01GM115622, Cancer Prevention and Research Institute of Texas Grants R1104, Welch Foundation Grant Q‐1798; the Center for Comparative Medicine, the Cytometry and Cell Sorting Core, the Center for Drug Discovery, and the Dan L. Duncan Cancer Center at Baylor College of Medicine; and the Texas Medical Center Digestive Diseases Center.