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，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过表达，其水平预测对治疗的反应。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，并在肾包膜下发育成PIN。在Rbnull干细胞中，Pim-1过表达诱导肾包膜模型中生长的肿瘤发生。Pim-1通过mTOR通路调节信号，为靶向癌症治疗提供了额外的机会。因此，该项目的目标是开发独特的Pim-1抑制剂，无论是否使用TOR蛋白激酶抑制剂（如雷帕霉素），都可以治疗前列腺癌。我们已经确定了一种新的化学型，可以在体外和完整细胞中抑制Pim-1蛋白激酶活性。在这个一期STTR项目中，我们将通过以下具体目标来研究开发具有抗癌活性的新型Pim-1抑制剂的可行性：1)利用药物和计算化学对Pim-1抑制剂进行优化；2)在体外和前列腺癌细胞中评价新化合物对皮姆-1的影响；3)评价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。这些特定目标的完成将为使用Pim-1抑制剂作为抗癌药物的可行性提供清晰的论证，并确定候选药物，以便在II期STTR项目中进一步开发。公共卫生相关性：Pim蛋白激酶是参与前列腺癌发病机制的关键酶。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。这些化合物的持续开发是为治疗前列腺癌提供重要新药的必要条件。

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.