Abstract A223: Novel drug development approach targeting STAT3 for sarcoma therapy using MLSD and drug reposition.
Authors: Liu Aiguo , Li Huameng , Xu Minghao , Zhao Zhenjiang , McWilliams Emily , Xu Yufang , Li Chenglong , Lin Jiayuh 
Published: June 2012

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in human cancer including rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma and has emerged as a viable molecular target for sarcoma treatment. Rhabdomyosarcoma is the most common soft tissue sarcoma in pediatric patients{Niu, 1999 #1867}. Osteosarcoma is the most commonly diagnosed primary malignant tumor of bone, which mainly affects adolescents and young adults. Ewing's sarcoma is the second most common primary bone malignancy in pediatric patients. Novel therapeutic approaches are needed for these childhood sarcomas if significant improvements in survival are to occur. To date, however, no known STAT3 inhibitors are available for the therapy of childhood sarcomas yet. Conventional high throughput screening and virtual docking drug discovery approaches identified many hits, but only a few of them may be developed into drugs. To accelerate STAT3 drug development, we used a novel drug discovery approach with multiple ligand simultaneous docking (MLSD), which we have developed and drug repositioning to search against FDA approved drug and experimental drug database in DrugBank. Using this new method, we identified the FDA-approved drug celecoxib (a COX-2 inhibitor) with a novel function to target STAT3 [Predictive STAT3 binding dissociation constant (Kd)=8.6μM]. In addition, a novel celecoxib analog (8A) was developed exhibiting stronger STAT3 binding (Predicted Kd=0.12 M; 71-fold stronger than celecoxib). Although 8A has stronger STAT3 binding, it has weaker COX-2 binding (521-fold weaker than celecoxib), suggesting its selectivity on STAT3 versus COX-2. Minimal COX-2 inhibition of 8A may reduce cardiovascular and gastrointestinal risks associated with COX-2 inhibitors. The ability of 8A to inhibit STAT3 was tested. 8A inhibited the P-STAT3 stimulated by IL-6 but not the induction of STAT1 phosphorylation by IFN-γ. 8A also inhibited the induction of STAT3 nuclear localization by IL-6, which could prevent STAT3 functions as a transcription factor. 8A inhibited STAT3 phosphorylation and resulted in the induction apoptosis on sarcoma cells as evidenced by caspase-3 cleavage. Further, 8A was more potent than celecoxib to inhibit STAT3 phosphorylation and induce apoptosis in sarcoma cells, which confirmed the stronger STAT3 binding energy than celecoxib. In summary, our study is the first report using MLSD and drug repositioning to develop drug-like STAT3 inhibitors. This novel method has a potential to significantly speed up the STAT3 drug development for the therapy of childhood sarcoma and possibly other types of human cancer express constitutive STAT3 signaling.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A223.