Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

• DOI: 10.1016/j.ejmech.2014.05.049
• Publication Date: 2014-05-22T15:22:17Z
• Authors: Haijun Chen; Zhengduo Yang; Chunyong Ding; Ailian Xiong; Christopher Wild; Lili Wang; Na Ye; Guoshuai Cai; Rudolfo M. Flores; Ye Ding; Qiang Shen; Jia Zhou
• Keywords: Models, Molecular; STAT3 Transcription Factor; 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; Administration, Oral; Mammary Neoplasms, Experimental; Mice, Nude; Antineoplastic Agents; Crystallography, X-Ray; 3. Good health; Small Molecule Libraries; Mice; 03 medical and health sciences; Cell Line, Tumor; Benzamides; Drug Discovery; MCF-7 Cells; Animals; Humans; Female; Drug Screening Assays, Antitumor; Cell Proliferation

In a continuing effort to develop orally bioavailable small-molecule STAT3 inhibitors as potential therapeutic agents for human cancer, a series of novel diversified analogues based on our identified lead compound HJC0149 (1) (5-chloro-N-(1,1-dioxo-1H-1λ(6)-benzo[b]thiophen-6-yl)-2-hydroxybenzamide, Eur. J. Med. Chem. 2013, 62, 498-507) have been rationally designed, synthesized, and pharmacologically evaluated. Molecular docking studies and biological characterization supported our earlier findings that the O-alkylamino-tethered side chain on the hydroxyl group is an effective and essential structural determinant for improving biological activities and druglike properties of these molecules. Compounds with such modifications exhibited potent antiproliferative effects against breast and pancreatic cancer cell lines with IC50 values from low micromolar to nanomolar range. Among them, the newly discovered STAT3 inhibitor 12 (HJC0416) displayed an intriguing anticancer profile both in vitro and in vivo (i.p. & p.o.). More importantly, HJC0416 is an orally bioavailable anticancer agent as a promising candidate for further development.