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

项目概要/摘要 使用激酶抑制剂来剖析和验证癌症信号传导通路内的靶向节点， 彻底改变了肿瘤药物的发现其中最有趣的目标是CAMKK 2，一种激酶 参与一系列重要的生物学功能，包括代谢稳态、蛋白质合成、细胞 运动性、基因转录、细胞存活和巨噬细胞活化。大量证据表明， CAMKK2及其调节的过程参与了具有重要病理意义的通路， 乳腺癌前列腺癌肝癌和胃癌目前迫切需要一种有效的、选择性的和体内的 活性CAMKK2化学探针，可用于确定CAMKK2在细胞信号传导中的作用并评估 CAMKK2抑制剂在相关人类疾病模型中的治疗潜力。在这里，我们提出一个 迭代的药物化学方法来开发在体内有效和选择性的CAMKK2抑制剂。我们 将使用这些新化合物来验证CAMKK 2作为肝脏，乳腺和前列腺的可行治疗靶点 癌使用独特的化合物设计策略，我们已经确定了几种有效的和选择性的化学品， 导致抑制CAMKK2。我们将使用以下方法将这些引线优化为体内活性CAMKK 2化学探针： 迭代药物化学（目标1）。目标1测定将集中于CAMKK 2针对分离的靶标的效力， CAMKK 2在细胞环境中的效力、激酶选择性和特性优化以产生分子 适合于体内使用。我们的新的选择性CAMKK 2抑制剂将在一系列疾病相关的 癌症细胞模型（Aim 2）。这些研究将探索CAMKK 2抑制对细胞增殖的影响， 集落形成、巨噬细胞活化和肿瘤微环境的重塑。我们将 评估我们优化的体内活性CAMKK 2探针在乳腺、前列腺和乳腺癌小鼠模型中的功效。 肝癌（Aim 3）。为了实现我们的目标，我们组建了一个合作的多学科团队， 在激酶抑制剂优化、CAMKK2信号传导和肿瘤生物学方面的经验。成功完成 该项目将提供高度优化的CAMKK 2靶向分子，并可能导致新的癌症药物 治疗

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.