Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: Promising agents against multiple myeloma

Brent D.G. Page, Danielle C. Croucher, Zhi Hua Li, Sina Haftchenary, Victor H. Jimenez-Zepeda, Jennifer Atkinson, Paul A. Spagnuolo, Yoong Lim Wong, Robert Colaguori, Andrew M. Lewis, Aaron D. Schimmer, Suzanne Trudel, Patrick T. Gunning

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3-4 years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3's SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.

Original languageEnglish (US)
Pages (from-to)7190-7200
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number18
DOIs
StatePublished - Sep 26 2013

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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