Enzalutamide resistance is a major obstacle in the treatment of metastatic, castration-resistant prostate cancer (mCRPC). Recently we developed a small-molecule lead compound GH501 and demonstrated its potent activity against bone metastatic prostate cancer cells. In this Phase I STTR application, we hypothesize that GH501 is a novel lead compound with nanomolar potency against enzalutamide-resistant and bone metastatic prostate cancer.
Two Aims are proposed.
In Aim 1, we will synthesize high-purity GH501 and determine the acute toxicity, pharmacokinetics and in vivo bioavailability/distribution of GH501 in rodent models;
in Aim 2, we will validate the in vivo efficacy of GH501 against mCRPC in clinically-relevant animal models. These studies will provide convincing rationale for us to continue the GH501 project at MetCure for further pre-clinical and clinical development. The project has important impact and translational potential in treating a lethal disease.
In this Phase I STTR application, we will develop a potent small-molecule drug GH501 to overcome enzalutamide resistance and treat bone metastatic prostate cancer, a major cause of cancer death in American men. This project has important impact in treating a lethal disease, reducing cancer morbidity and improving healthcare in the United States and globally.
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Yang, Yang; Mamouni, Kenza; Li, Xin et al. (2018) Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer. Mol Cancer Ther 17:1859-1870 |
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Yang, Yang; Li, Xin; Mamouni, Kenza et al. (2017) Mifepristone Has Limited Activity to Enhance the In Vivo Efficacy of Docetaxel and Enzalutamide Against Bone Metastatic and Castration-Resistant Prostate Cancer. Anticancer Res 37:6235-6243 |