Creation of in vivo active chemical probes for CAMKK2 to treat cancer

创建 CAMKK2 体内活性化学探针来治疗癌症

基本信息

批准号：
9751258
负责人：
David Harold Drewry
金额：
$ 63.04万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751258
关键词：
Animal Model Antineoplastic Agents Bioavailable Biochemistry Biological Biological Assay Biological Process Biology Breast Cancer Model Cell Proliferation Cell Survival Cell model Cell physiology Chemicals Clinic Clinical Clinical Research Collaborations Collection Communities Data Dendritic Cells Development Disease Drug Kinetics Enzymes Genetic Genetic Transcription Goals Homeostasis Human Immune Investigation Lead Macrophage Activation Maintenance Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of prostate Medicine Metabolic Metabolism Myeloid-derived suppressor cells Neoplasm Metastasis Oral Pathologic Pathologic Processes Pathway interactions Pharmaceutical Chemistry Pharmacology Phosphotransferases Primary Neoplasm Process Property Protein Biosynthesis Proteins Publishing Research Personnel Role Signal Pathway Signal Transduction Solubility Testing Therapeutic Therapeutic Effect Tumor Biology Validation Work anti-tumor immune response anticancer activity cancer therapy cell motility cell type cellular targeting design drug development drug discovery enzyme activity experience human disease human model in vivo inhibitor/antagonist kinase inhibitor macrophage malignant breast neoplasm malignant stomach neoplasm mouse model multidisciplinary novel novel anticancer drug oncology programs screening therapeutic target tool translation to humans tumor tumor growth tumor microenvironment

项目摘要

Project Summary / Abstract The use of kinase inhibitors to dissect and validate targetable nodes within cancer signaling pathways has revolutionized oncology drug discovery. Among the most interesting targets identified is CAMKK2, a kinase involved in a range of critical biological functions including metabolic homeostasis, protein synthesis, cell motility, gene transcription, cell survival, and macrophage activation. Substantial evidence demonstrates that CAMKK2 and the processes it regulates are involved in pathways of significant pathological importance in breast, prostate, hepatic, and gastric cancers. There is an immediate need for potent, selective, and in vivo active CAMKK2 chemical probes that can be used to define the roles of CAMKK2 in cell signaling and evaluate the therapeutic potential of CAMKK2 inhibitors in relevant models of human disease. Here we propose an iterative medicinal chemistry approach to develop CAMKK2 inhibitors that are potent and selective in vivo. We will use these new compounds to validate CAMKK2 as a viable therapeutic target for liver, breast, and prostate cancer. Using a unique compound design strategy, we have identified several potent and selective chemical leads that inhibit CAMKK2. We will optimize these leads into in vivo active CAMKK2 chemical probes using iterative medicinal chemistry (Aim 1). Aim 1 assays will focus on CAMKK2 potency against the isolated target, CAMKK2 potency in a cellular context, kinase selectivity, and optimization of properties to create molecules suitable for in vivo use. Our new selective CAMKK2 inhibitors will be evaluated in a range of disease-relevant cancer cellular models (Aim 2). These studies will explore the effects of CAMKK2 inhibition on cell proliferation, colony formation, macrophage activation, and on the remodeling of the tumor microenvironment. We will evaluate the efficacy of our optimized in vivo active CAMKK2 probes in mouse models of breast, prostate, and liver cancer (Aim 3). To accomplish our goals we have assembled a collaborative, multidisciplinary team with experience in kinase inhibitor optimization, CAMKK2 signaling, and tumor biology. Successful completion of this project will provide highly optimized CAMKK2-targeting molecules and may lead to new drugs for cancer treatment.

项目摘要 /摘要使用激酶抑制剂在癌症信号通路内剖析和验证可靶向节点的使用已有革命性的肿瘤药物发现。在确定的最有趣的目标中，是激酶CaMKK2 参与一系列关键的生物学功能，包括代谢稳态，蛋白质合成，细胞运动，基因转录，细胞存活和巨噬细胞激活。大量证据表明 CAMKK2及其调节的过程参与了具有重要病理重要性的途径乳房，前列腺，肝和胃癌。立即需要有效，选择性和体内可用于定义CAMKK2在细胞信号传导中的作用并评估的活动CAMKK2化学探针 CAMKK2抑制剂在相关的人类疾病模型中的治疗潜力。在这里我们提出一个迭代药物化学方法是开发在体内有效且有选择性的CAMKK2抑制剂的方法。我们将使用这些新化合物来验证CAMKK2作为肝，乳房和前列腺的可行治疗靶点癌症。使用独特的复合设计策略，我们确定了几种有效的选择性化学物质引导抑制CAMKK2。我们将使用这些铅优化这些铅的体内活性CAMKK2化学探针迭代药物化学（AIM 1）。 AIM 1分析将重点放在针对孤立目标的CAMKK2效力上 CAMKK2在细胞环境，激酶选择性和特性优化以创建分子的效力适用于体内使用。我们的新选择CAMKK2抑制剂将在一系列疾病中进行评估癌细胞模型（AIM 2）。这些研究将探讨CAMKK2抑制对细胞增殖的影响，菌落形成，巨噬细胞激活以及肿瘤微环境的重塑。我们将评估我们优化的体内活性CAMKK2探针在乳房，前列腺和肝癌（AIM 3）。为了实现我们的目标，我们已经组建了一个合作，多学科团队具有激酶抑制剂优化，CAMKK2信号传导和肿瘤生物学的经验。成功完成该项目将提供高度优化的CAMKK2靶向分子，并可能导致癌症的新药治疗。