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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-02, Vol.76 (3), p.652-663
• Main Authors: Yue, Peibin, Lopez-Tapia, Francisco, Paladino, David, Li, Yifei, Chen, Chih-Hong, Namanja, Andrew T, Hilliard, Tyvette, Chen, Yuan, Tius, Marcus A, Turkson, James
• Format: Article
• Language: English
• Subjects: Animals; Benzoates - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Humans; Hydroxamic Acids - pharmacology; Male; MCF-7 Cells; Mice; Mice, Nude; NIH 3T3 Cells; Signal Transduction; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Transfection
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-14-3558

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.