Abstract 3801: Small molecule inhibitor of Stat3 induces antitumor cell effects in vitro and antitumor effects in vivo against human glioma or breast cancer model

Abstract

Abstract Aberrant activation of signal transducer and activator of transcription 3 (Stat3) is prevalent in many human cancers. Compelling evidence shows that constitutively-active Stat3 constitutes a point of convergence in oncogenic tyrosine kinase signaling, functioning as a master regulator of events crucial for tumorigenesis and malignant progression. We show herein that the small-molecule, SH5-07 abrogates constitutive activation of Stat3 and Stat3-dependent functions in human glioma and breast cancer cells. SH5-07 inhibits in vitro Stat3 DNA-binding activity with an IC50 value of 3.9 μM. Treatment of human glioma U251MG and breast cancer MDA-MB-231 cells that harbor aberrantly-active Stat3 with low micromolar SH5-07 blocks Stat3 phosphorylation, DNA-binding, and transcriptional activities in a time and dose-dependent manner. By contrast, SH5-07 shows little or no effect on the induction of pJAK2, pSrc, pErk1/2, and pShc in glioma and breast cancer cells. SH5-07 preferentially inhibited viability of human glioma and breast cancer cells that harbor aberrant Stat3 activity, with IC50 of 1.1-5.2 µM, compared to IC50 of 6.0-10.8 µM for cells that do not. Inhibition of aberrantly-active Stat3 by SH5-07 preferentially suppresses the anchorage-dependent and independent growth, induces apoptosis, and blocks migration and invasion in vitro of human glioma and breast cancer cells that harbor constitutively-active Stat3. Moreover, oral administration of SH5-07 inhibits the growth of human breast tumor xenografts in mice. Data together indicates SH5-07 is a promising small-molecule Stat3 inhibitor and a suitable drug candidate for clinical development. Citation Format: Peibin Yue, Francisco Lopez-Tapia, Marcus Tius, James Turkson. Small molecule inhibitor of Stat3 induces antitumor cell effects in vitro and antitumor effects in vivo against human glioma or breast cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3801. doi:10.1158/1538-7445.AM2014-3801