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

Abstract

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-1λ6-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.

Evolutions in fragment-based drug design: the deconstruction–reconstruction approach

“…After deconstruction of privileged fragments from known STAT3 inhibitors to generate a small fragment library (Figure 2A), several novel scaffolds were reconstructed and chemically synthesized (Figure 2B). Further pharmacological evaluation led to the identification of several compounds, including HJC0123, HJC0149, and HJC0371, as advanced chemical leads for further optimization [26]. The results from the predicted binding mode of HJC0123 with the SH2 domain of STAT3 (Figure 2C) are in full agreement with previous established structure–activity relation (SAR) data [25].…”

Discovery and development of natural product oridonin-inspired anticancer agents

“…With the established SAR information of explored oridonin derivatives (Fig. 12) and useful chemical probes [106], fragment-based drug design (FBDD) [107–112] by taking advantage of privileged fragments, especially the critical pharmacophores in marketable and clinical trial natural drugs, may provide an additional strategy to develop more effective and drug-like oridonin derivatives with higher potency, better oral bioavailability and safety performance.…”

STAT3 inhibition suppresses hepatic stellate cell fibrogenesis: HJC0123, a potential therapeutic agent for liver fibrosis

“…13 This method allows for synthesis of new molecules with enhanced drug-likeness by chemically merging privileged fragments from small molecule libraries. 14–17 Using FBDD, our team previously designed, synthesized and characterized a new STAT3 inhibitor, compound HJC0123 (Figure 1A). This small molecule induces growth arrest and apoptosis in MDA-MB-231 breast cancer cells.…”