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Novel Inhibitors of Pim Protein Kinases

Pim 蛋白激酶的新型抑制剂

基本信息

批准号：
7743696
负责人：
Andrew S Kraft
金额：
$ 25.79万
依托单位：
VORTEX BIOTECHNOLOGY CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-07 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7743696
关键词：
3-Dimensional Address Antineoplastic Agents Apoptosis Attenuated Cancer Center Cell Proliferation Cell model Cells Chemotherapy-Oncologic Procedure Collagen Development Disease Dose Drug Kinetics Enzymes Evaluation Fibrous capsule of kidney Goals Growth In Vitro Intraepithelial Neoplasia Isoenzymes Lead Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Metastatic Prostate Cancer Methods Modeling Mus Neoplasms Oncogenes Oncogenic Pathogenesis Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphorylation Process Property Prostate Protein Kinase Protein Kinase Inhibitors Role Screening for cancer Series Signal Transduction Sirolimus Small Business Technology Transfer Research South Carolina Stem cells Structure-Activity Relationship Testing Treatment Efficacy Universities anticancer activity cancer cell cancer therapy chemotherapy computational chemistry drug candidate experience human FRAP1 protein in vitro activity in vivo inhibitor/antagonist lymphoid neoplasm mouse model neoplastic cell novel overexpression programs protein kinase inhibitor proto-oncogene protein pim public health relevance research clinical testing research study response secondary outcome small molecule small molecule libraries tumor tumor growth tumor progression

项目摘要

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.

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，其水平可预测对治疗的反应。Pim-1过表达的小鼠前列腺干细胞在3-D胶原培养中表现出异常生长，当置于肾包膜下时发育成PIN。在Rb null干细胞中，Pim-1过表达诱导在肾包膜模型中生长的坦率瘤形成。Pim-1通过mTOR通路调节信号传导，为靶向癌症治疗提供了额外的机会。因此，该计划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。我们已经确定了一个新的化学型，抑制Pim-1蛋白激酶活性在体外和完整的细胞。在这个I期STTR项目中，我们将通过以下具体目标来解决开发具有抗癌活性的新Pim-1抑制剂的可行性：1）使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的影响;和3）评估Pim-1抑制剂的体内抗癌功效。这些研究为合成和评价前列腺癌化疗新兴靶点的新抑制剂提供了有效的方法。这些特定目标的完成将清楚地证明使用Pim-1抑制剂作为抗癌剂的可行性，并确定在II期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Pim激酶的新抑制剂的方法。这些化合物的持续开发对于提供用于治疗前列腺癌的重要新药是必要的。