Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity

Angew Chem Int Ed Engl. 2015 Oct 26;54(44):13085-9. doi: 10.1002/anie.201506889. Epub 2015 Sep 7.

Abstract

Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.

Keywords: anti-tumor agents; leukemia; protein modifications; rhodium; stat3.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Binding Sites / drug effects
  • Catalysis
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Rhodium / chemistry*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Antineoplastic Agents
  • Naphthalenes
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Sulfonamides
  • Rhodium