Abstract 4792: Azetidine functionalized small-molecules potently inhibit STAT3 signaling and block tumor growth in human breast cancer xenografts

The development of inhibitors of Signal transducer and activator of transcription (STAT) 3 for clinical application has faced significant challenges and to date there are no suitable STAT3 small molecule inhibitors in the clinic. We report a novel class of azetidine-based small molecules that potently and preferentially inhibit STAT3 DNA-binding activity in vitro, with IC50 of 300-800 nM, compared to IC50 of 17 μM or higher against STAT1 DNA-binding activity. In the human breast cancer MDA-MB-231 and MDA-MB-468 cells treated with the azetidine compounds, including H182, constitutive STAT3 DNA-binding activity and tyrosine phosphorylation were strongly inhibited in both time- and dose-dependent manner. By contrast, the azetidine compounds showed little effects on EGF-induced STAT1 activity, Ras-Raf-MEK-ERK or other STAT3-independent signaling pathways, or on other SH2 domain-containing proteins. Furthermore, H182 and other azetidine compounds strongly inhibited viability, anchorage-dependent and -independent growth, and colony survival of the human breast cancer cells, with IC50 of 1.0 - 1.9 μM, compared to the IC50 of 3.8 - 8.1 μM against the viability and growth of the immortalized breast epithelial MCF-10A cells. The migration of breast cancer cells in vitrowere similarly inhibited by treatment with low concentrations of H182 for 18 h, without changes in viable cell number. Analysis of STAT3 downstream genes show that the expression of VEGF and survivin were significantly suppressed in breast cancer cells treated with the azetidine compounds. In vivo evaluation of antitumor efficacy shows H182 inhibited growth of human breast tumor xenografts. Studies together identify the azetidine-functionalized small molecules as potential candidate compounds for clinical development as novel therapeutic agents for human breast and other cancers that harbor aberrantly-active STAT3. Citation Format: Peibin Yue, Francisco Lopez-Tapia, Wenzhen Fu, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Azetidine functionalized small-molecules potently inhibit STAT3 signaling and block tumor growth in human breast cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4792.