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

项目摘要/摘要 使用激酶抑制剂来解剖和验证癌症信号通路中的靶向结节 革命性的肿瘤学药物发现。在发现的最有趣的靶标中，有一种叫CAMKK2，它是一种激酶 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激活。确凿的证据表明 CAMKK2及其调控的过程参与了具有重要病理意义的信号转导通路。 乳腺癌、前列腺癌、肝癌和胃癌。迫切需要有效的、选择性的和活体内的 活性CAMKK2化学探针，可用于确定CAMKK2在细胞信号转导中的作用并评估 CAMKK2抑制剂在相关人类疾病模型中的治疗潜力。在这里，我们提出一种 迭代药物化学方法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CAMKK2作为治疗肝脏、乳腺和前列腺的可行靶点 癌症。使用一种独特的化合物设计策略，我们已经确定了几种有效和选择性的化学物质 抑制CAMKK2的铅。我们将优化这些线索，使其成为体内活性的CAMKK2化学探针 迭代药物化学(目标1)。AIM 1检测将集中于CAMKK2对分离靶标的效力， CAMKK2在细胞环境中的效力、激酶的选择性和创造分子的性质的优化 适合活体使用。我们新的选择性CAMKK2抑制剂将在一系列与疾病相关的药物中进行评估 肿瘤细胞模型(AIM 2)。这些研究将探索抑制CAMKK2对细胞增殖的影响， 集落形成，巨噬细胞激活，以及肿瘤微环境的重建。我们会 评价我们优化的活体活性CAMKK2探针在小鼠乳腺、前列腺和 肝癌(目标3)。为了实现我们的目标，我们组建了一个协作、多学科的团队， 在激酶抑制剂优化、CAMKK2信号和肿瘤生物学方面有经验。成功完成 该项目将提供高度优化的CAMKK2靶向分子，并可能导致治疗癌症的新药 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.