Novel STAT3 drug development for childhood osteosarcoma therapy using drug repositioning
Osteosarcoma is the most common malignant bone tumor in kids. Osteosarcoma frequently express constantly activated STAT3, which is required for cancer progression. Therefore, the development of STAT3 inhibitors for osteosarcoma therapy is desirable and should have high clinical impact. We have developed a novel STAT3 drug discovery approach using multiple ligand simultaneous docking (MLSD) and drug repositioning. MLSD can check multiple fragments from existing drugs already approved for use in humans for docking to STAT3 binding sites. Drug repositioning refers to reusing existing drugs for new targets, thus greatly increase the likelihood of bringing lead STAT3 inhibitors to clinical application sooner. Using this method, we demonstrated that FDA-approved drug celecoxib has a new function against STAT3. Furthermore, we developed 8A as a novel celecoxib analog with stronger activity against STAT3, making it an excellent lead drug. Two novel 8A analogs will be synthesized to (I) enhance the tumor suppression capacity by increasing STAT3 inhibition; (II) maintain the drug properties to those of celecoxib to facilitate translational into clinical drugs. Two new analogs will be tested in human and dog osteosarcoma cells and in mouse tumor models. The future plans lead to potential clinical trials: 8A analog will be further tested in dog clinical trials with osteosarcoma. The dog osteosarcoma shares many clinical similarities to human osteosarcoma and is a very valuable tumor model on drug efficacy and safety prior to human clinical trials. The clinical trials in children with osteosarcoma will be developed after the completion of dog osteosarcoma trials.