Norstictic Acid Is a Selective Allosteric Transcriptional Regulator

  • J Am Chem Soc. 2021 Jun 30;143(25):9297-9302. doi: 10.1021/jacs.1c03258.
Julie M Garlick  1  2 ,  Steven M Sturlis  1  2 ,  Paul A Bruno  1  2 ,  Joel A Yates  3 ,  Amanda L Peiffer  1  4 ,  Yejun Liu  1  4 ,  Laura Goo  3 ,  LiWei Bao  3 ,  Samantha N De Salle  1  4 ,  Giselle Tamayo-Castillo  5 ,  Charles L Brooks 3rd  2  4  6 ,  Sofia D Merajver  3 ,  Anna K Mapp  1  2  4
Affiliations
  • 1. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Internal Medicine, Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
  • 4. Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5. CIPRONA and School of Chemistry, University of Costa Rica, 11501 San Jose, Costa Rica.
  • 6. Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 34137598 DOI: 10.1021/jacs.1c03258
Abstract

Inhibitors of transcriptional protein-protein interactions (PPIs) have high value both as tools and for therapeutic applications. The PPI network mediated by the transcriptional coactivator Med25, for example, regulates stress-response and motility pathways, and dysregulation of the PPI networks contributes to oncogenesis and metastasis. The canonical transcription factor binding sites within Med25 are large (∼900 Å2) and have little topology, and thus, they do not present an array of attractive small-molecule binding sites for inhibitor discovery. Here we demonstrate that the depsidone natural product norstictic acid functions through an alternative binding site to block Med25-transcriptional activator PPIs in vitro and in Cell Culture. Norstictic acid targets a binding site comprising a highly dynamic loop flanking one canonical binding surface, and in doing so, it both orthosterically and allosterically alters Med25-driven transcription in a patient-derived model of triple-negative breast Cancer. These results highlight the potential of Med25 as a therapeutic target as well as the inhibitor discovery opportunities presented by structurally dynamic loops within otherwise challenging proteins.

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