Small-molecule therapy for metastatic prostate cancer

Enzalutamide耐药是治疗转移性去势抵抗性前列腺癌的主要障碍 （mCRPC）。最近，我们开发了一种小分子先导化合物GH501，并证明了其有效的 抗骨转移性前列腺癌细胞的活性。在第一阶段STTR申请中，我们假设 GH501是一种新型先导化合物，具有纳摩尔级抗Enzalutamide耐药和骨转移的效力 前列腺癌提出了两个目标。在目标1中，我们将合成高纯度的GH501，并测定其 GH501在啮齿动物模型中的急性毒性、药代动力学和体内生物利用度/分布;在目标2中，我们 将在临床相关动物模型中验证GH501对mCRPC的体内疗效。这些研究 将为我们在MetCure继续GH501项目进行进一步的临床前研究提供令人信服的理由， 临床发展。该项目在治疗致命疾病方面具有重要的影响和转化潜力。

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.