Small Molecule Activators of PP2A (SMAPs) for Prostate Cancer Therapy

 描述(申请人提供)：前列腺癌是美国男性癌症相关死亡的第二大原因。除了受影响和失去的生活负担外，预计2014年将有超过192,280例前列腺癌新病例。明确界定这种疾病的遗传基础的必要性是显而易见的。肿瘤发生的标志之一是多种细胞激酶和促生长核激素受体信号的异常激活。持续的致癌激活需要协调肿瘤抑制基因的失活，如蛋白磷酸酶，以允许信号的传播。虽然通过开发核激素拮抗剂(如MDV3100)或激酶抑制剂来抑制致癌信号已经导致了一些治疗成功，但大多数表现出适度的疗效，导致最终的肿瘤耐药。肿瘤抑制基因的治疗激活在很大程度上仍未被探索。我们已经开发了一系列针对蛋白磷酸酶的新药，具有良好的药代动力学，并且没有明显的毒性。对这些化合物的表征表明，它们能够同时抑制前列腺癌细胞系和小鼠模型中的MYC和AR效应通路。我们的研究代表着进入这一新领域的第一步，并强调了开发其他蛋白磷酸酶和肿瘤抑制蛋白的小分子激活剂的潜力，用于治疗前列腺癌以及更广泛的其他癌症。

 DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer-related death among males in the United States. Beyond the burden in lives affected and lost, more than 192,280 new cases of prostate cancer are projected in 2014. The need to define the genetic basis of this disease is clear. One of the hallmarks of oncogenesis is the aberrant activation of various cellular kinases and growth promoting nuclear hormone receptor signaling. Sustained oncogenic activation requires coordinate inactivation of tumor suppressor genes, such as protein phosphatases, to allow propagation of signaling. Although the inhibition of oncogenic signaling through the development of nuclear hormone antagonists (such as MDV3100) or kinase inhibitors has resulted in some therapeutic success, most exhibit modest efficacy, leading to eventual tumor resistance. The therapeutic activation of tumor suppressor genes has remained largely unexplored. We have developed a series of novel drugs that uniquely target protein phosphatases and possess favorable pharmacokinetics and no significant toxicity. Characterization of these compounds revealed their ability to simultaneously inhibit both the MYC and AR effector pathways in prostate cancer cell lines and mouse models. Our studies represent a first step into that new territory and highlight the potential for the development of small molecule activators of other protein phosphatases and tumor suppressor proteins for the treatment of prostate cancer specifically and other cancers more generally.