Fragment-based drug design and identification of HJC0123 , a novel orally bioavailable STAT3 inhibitor for cancer therapy

Abstract

Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC 50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy.

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

“…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]. Further biological evaluations resulted in the discovery of HJC0123 as an orally bioavailable anticancer drug candidate targeting STAT3 (Figure 2D).…”

“…Despite these significant advances, no US Food and Drug Administration (FDA)-approved STAT3 inhibitor drugs are currently available in the clinic because of their limited potency, efficacy and drug-like properties. Figure 2 illustrates the discovery of HJC0123, an orally bioavailable drug candidate that is now in preclinical studies for the treatment of breast cancer and other malignancies [25]. 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).…”

Activities of N , N ′-Diarylurea MMV665852 Analogs against Schistosoma mansoni

“…For in vitro tests, compounds were prepared as 10 mM stock solutions in dimethyl sulfoxide (DMSO) (Sigma-Aldrich). For in vivo tests, compound 37 (15) was synthesized according to the methods of Chen et al (16) and Hwang et al (17). The culture media were prepared from medium 199 or RPMI 1640 (Life Technologies) with L-glutamine (Sigma-Aldrich), heatinactivated fetal calf serum (FCS), penicillin, and streptomycin, which were purchased from LuBioScience.…”

Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach

“…Computer screening proved to be effective in the identification of new STAT3 SH2 domain binding inhibitors, blocking STAT3 dimerization, including some well-known compounds like STA-21 9 , S3I-201 10 and STX-0119 11 , which have been all identified through in silico screening purely relied on the docking of compound libraries into the STAT3 SH2 domain. Other examples of docking-based virtual screening (VS) studies are reported in literature [12][13][14][15] and recently some fragment-based drug design studies, combining docking and synthesis, have been published 16,17 . However, different computational approaches, like QSAR studies and pharmacophore screening, have been rarely applied 18,19 .…”