Small-molecule therapy for metastatic castration-resistant prostate cancer

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Metastatic, castration-resistant prostate cancer (mCRPC) is lethal with no cure. Although current treatments initially prolong survival, patients generally relapse and develop therapeutic resistance, which is a major obstacle in the management of prostate cancer. It is imperative to develop efficacious therapies to treat lethal mCRPC and improve the survivorship of patients. During the Phase I STTR period, we identified a novel small- molecule inhibitor of S phase kinase-associated protein 1 (Skp1) – F-Box protein (FBP) interaction, namely GH501, that exhibits nanomolar potency against mCRPC and a broad spectrum of human cancer cell lines. We have conducted pilot studies on the preclinical safety, pharmacokinetics, distribution and efficacy of GH501 against mCRPC. In this Phase II STTR project, we will test the central hypothesis that our lead compound GH501 is a first-in-class Skp1-FBP inhibitor that effectively treats mCRPC. The proposed studies are built upon: (1) an urgent and unmet medical need to develop new interventions for lethal mCRPC, (2) an imperative need to identify new therapeutic targets in mCRPC; and (3) strong preclinical evidence supporting GH501 as a novel and effective inhibitor of mCRPC. The overall objective is to conduct Investigational New Drug (IND)- enabling toxicology and efficacy studies on GH501 as a drug candidate for the treatment of lethal mCRPC. In Aim 1, we will develop an oral formulation of GH501 and test the hypothesis that GH501 has excellent safety and drug-like properties in preclinical models. In Aim 2, we will validate the mechanism of action of GH501 and test the hypothesis that as a novel Skp1 inhibitor, GH501 is efficacious against mCRPC in clinically-relevant xenograft models. Completion of the proposed project and follow-up preclinical studies will allow us to prepare an IND application within the next 3~4 years to advance GH501 into human trials. This highly innovative, translational project could have a significant impact in reducing prostate cancer mortality and morbidity.