Novel Inhibitors of Pim Protein Kinases

描述(由申请人提供)：越来越多的证据表明，蛋白激酶Pim-1是前列腺癌进展的主要驱动因素，也可能是对化疗的反应。PIM-1在早期前列腺上皮内瘤变和转移性前列腺癌中高表达，其水平可预测对治疗的反应。过表达PIM-1的小鼠前列腺干细胞在三维胶原培养中表现出异常生长，当放置在肾被膜下时发展为PIN。在Rbnul干细胞中，当Pim-1过表达时，当生长在肾包膜模型中时，会诱导肿瘤的发生。PIM-1通过mTOR通路调节信号，为靶向癌症治疗提供额外的机会。因此，该计划的目标是开发独特的Pim-1抑制剂，在使用或不使用TOR蛋白激酶抑制剂(如雷帕霉素)的情况下，该药物可用于治疗前列腺癌。我们已经确定了一种新的化学类型，它在体外和完整细胞中都能抑制Pim-1蛋白激酶的活性。在这个第一阶段的STTR项目中，我们将通过以下具体目标来研究开发新的具有抗癌活性的Pim-1抑制剂的可行性：1)利用药物和计算化学优化Pim-1抑制剂；2)评估新化合物在体外和前列腺癌细胞中对Pim-1的作用；以及3)评估Pim-1抑制剂的体内抗癌效果。这些研究为前列腺癌化疗新靶点的新抑制剂的合成和评价提供了一个有效的过程。这些具体目标的完成将清楚地证明使用PIM-1抑制剂作为抗癌药物的可行性，并确定在第二阶段STTR项目中进一步开发的候选药物。公共卫生相关性：Pim蛋白激酶是前列腺癌发病机制中的关键酶。在这个项目中，我们开发了合成和测试新的Pim激酶抑制剂的方法。继续开发这些化合物对于为前列腺癌的治疗提供重要的新药是必要的。

DESCRIPTION (provided by applicant): There is a growing body of evidence that implicates the protein kinase Pim-1 as a major driver of prostate cancer progression, and perhaps response to chemotherapy. Pim-1 is overexpressed in early prostate intraepithelial neoplasia and metastatic prostate cancer, and its levels predict response to therapy. Pim-1-overexpressing mouse prostate stem cells demonstrate abnormal growth in 3-D collagen cultures, and develop into PIN when placed under the renal capsule. In Rbnull stem cells, Pim-1 overexpression induces frank neoplasia when grown in the renal capsule model. Pim-1 modulates signaling through the mTOR pathway, providing additional opportunities for targeted cancer therapy. Therefore, the goal of this program is to develop unique inhibitors of Pim-1 that will function, with or without a TOR protein kinase inhibitor such as rapamycin, to treat prostate cancer. We have identified a new chemotype that inhibits Pim-1 protein kinase activity both in vitro and in intact cells. In this Phase I STTR project, we will address the feasibility of developing new Pim-1 inhibitors with anticancer activity through the following Specific Aims: 1) To optimize the Pim-1 inhibitors using medicinal and computational chemistry; 2) To evaluate the effects of the new compounds on Pim-1 in vitro and in prostate cancer cells; and 3) To evaluate the anticancer efficacy of Pim-1 inhibitors in vivo. These studies provide an efficient process for the synthesis and evaluation of new inhibitors of an emerging target for prostate cancer chemotherapy. Completion of these Specific Aims will provide a clear demonstration of the feasibility of using Pim-1 inhibitors as anticancer agents, and identify the drug candidate for further development in a Phase II STTR project. PUBLIC HEALTH RELEVANCE: The Pim protein kinases are critical enzymes involved in the pathogenesis of prostate cancer. In this project, we have developed methods for synthesizing and testing new inhibitors of Pim kinases. Continued development of these compounds is necessary to provide important new drugs for the treatment of prostate cancer.