2. Academic Validation
  3. Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo

Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo

  • Cancer Res. 2016 Feb 1;76(3):652-63. doi: 10.1158/0008-5472.CAN-14-3558.
Peibin Yue 1,  Francisco Lopez-Tapia 2,  David Paladino 1,  Yifei Li 3,  Chih-Hong Chen 3,  Andrew T Namanja 3,  Tyvette Hilliard 1,  Yuan Chen 3,  Marcus A Tius 2,  James Turkson 4
Affiliations

Affiliations

  • 1 Natural Products and Experimental Therapeutics, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii. Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii.
  • 2 Natural Products and Experimental Therapeutics, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii. Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii. Department of Chemistry, University of Hawaii, Manoa, Honolulu, Hawaii.
  • 3 Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California.
  • 4 Natural Products and Experimental Therapeutics, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii. Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii. jturkson@cc.hawaii.edu.
PMID: 26088127 DOI: 10.1158/0008-5472.CAN-14-3558
Abstract

STAT3 offers an attractive target for Cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate Cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and Survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA-binding activities, STAT3-independent gene transcription, or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast, and prostate Cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast Cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates for further development as Cancer therapeutics.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100494
    ≥98.0%, STAT3 抑制剂
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