Targeting Oncogenic Ras-MAPK Signaling Complexes via the Scaffold KSR

通过支架 KSR 靶向致癌 Ras-MAPK 信号复合物

基本信息

批准号：
10341106
负责人：
Arvin Dar
金额：
$ 40.91万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341106
关键词：
Allosteric Regulation Animal Model Animals Binding Biochemical Biological Assay Cancer Model Cancer Patient Cancer cell line Cell Line Chemicals Clinical Colorectal Complex Data Dimerization Disease Disease model Drug resistance Excretory function Feedback Goals Grant Heterodimerization Human In Vitro Investigation KRAS2 gene KSR gene Lead Ligands MAP3K1 gene MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Metabolism Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Molecular Conformation Mutation Nature Neoplasm Metastasis Oncogenic Pathway interactions Patients Pharmaceutical Chemistry Pharmacology Phosphotransferases Point Mutation Publishing Ras Signaling Pathway Resistance Roentgen Rays Role Series Signal Pathway Signal Transduction Structure Testing Therapeutic Therapeutic Index Work absorption analog antagonist base biological systems cancer initiation cancer subtypes cancer therapy design drug discovery experimental study gain of function genetic approach improved in silico in vivo inhibitor insight member mutant novel novel strategies patient population pharmacophore raf Kinases reconstitution scaffold small molecule targeted treatment therapeutic target tool tumor

项目摘要

Kinase suppressor of RAS (KSR) is a mitogen-activated protein kinase (MAPK) scaffold that is subject to allosteric regulation through dimerization with RAF. Studies in model organisms suggest that direct targeting of KSR could have important therapeutic implications for cancer therapy; however, testing this hypothesis through pharmacological approaches has been difficult owing to a lack of small molecule antagonists of KSR function. We have recently identified a promising set of lead compounds that bind directly to KSR to antagonize oncogenic RAS-MAPK signaling (Dhawan et al., Nature, 2016). This unique class of small molecules, which operate through stabilization of the KSR inactive state (KSRi), antagonize RAS-MAPK signaling by impeding RAF-KSR heterodimerization and conformational changes required for activation of the RAS-effector kinase MEK. Furthermore, we have found that KSRi has the potential to increase the efficacy of currently available MAPK inhibitors (including MEK inhibitors) by increasing therapeutic index, thereby expanding the potential utility of currently available MAPK inhibitors to treat patients with RAS-mutant cancers. Our preliminary studies have been based on in vitro studies, including reconstitution assays, cell line studies, and crystallographic analysis. In this proposal, we build upon our early leads so to create novel chemical probes that would be suitable for in vivo experiments. Compounds that emerge from this work will be valuable tools for the investigation of RAS-MAPK mechanisms, targets, and therapeutics. Furthermore, we will investigate direct targeting of KSR as a mechanism to inhibit deregulated RAS-MAPK pathway signaling within patient-derived and drug resistant cancer models. The RAS-MAPK pathway is activated in approximately 25% of human cancers, most often through point mutations in K-RAS. Deregulation of the RAS-MAPK pathway in patients is believed to be a major determinant of cancer initiation, progression, metastases, and often resistance to targeted therapies. Certain subtypes of cancer show a high percentage of RAS mutations; it is estimated that 95% of pancreatic cancers, 35% of colorectal, and 25% of lung cancers are dependent on mutant RAS-MAPK signaling. Currently, there are limited therapeutic options for these large patient populations. Small molecule targeting of KSR offers a novel approach to modulate RAS signaling pathways in disease, which if successful, could impact a high number of cancer patients.

RAS 激酶抑制因子 (KSR) 是一种丝裂原激活蛋白激酶 (MAPK) 支架，受通过与 RAF 的二聚化进行变构调节。对模式生物的研究表明，直接靶向 KSR 可能对癌症治疗具有重要的治疗意义；然而，通过测试这个假设由于缺乏 KSR 功能的小分子拮抗剂，药理学方法一直很困难。我们最近发现了一组有前途的先导化合物，它们直接与 KSR 结合以拮抗致癌 RAS-MAPK 信号传导（Dhawan 等人，Nature，2016）。这种独特的小分子类别，通过稳定 KSR 非活性状态 (KSRi) 来发挥作用，通过阻碍来拮抗 RAS-MAPK 信号传导激活 RAS 效应激酶所需的 RAF-KSR 异二聚化和构象变化甲乙酮。此外，我们发现 KSRi 有潜力提高现有药物的功效 MAPK抑制剂（包括MEK抑制剂）通过提高治疗指数，从而扩大潜力目前可用的 MAPK 抑制剂用于治疗 RAS 突变癌症患者的效用。我们的初步研究基于体外研究，包括重构测定、细胞系研究和晶体学分析。在这个提案中，我们以我们的早期线索为基础，创造出新颖的化学探针适合体内实验。这项工作中产生的化合物将成为有价值的工具 RAS-MAPK 机制、靶点和治疗方法的研究。此外，我们将研究 KSR 的直接靶向作为抑制 RAS-MAPK 失调的机制患者来源的癌症模型和耐药癌症模型中的通路信号传导。 RAS-MAPK 途径是在大约 25% 的人类癌症中被激活，最常见的是通过 K-RAS 的点突变。放松管制患者体内 RAS-MAPK 通路的变化被认为是癌症发生、进展的主要决定因素，转移，并且通常对靶向治疗产生耐药性。某些癌症亚型的比例很高 RAS突变；据估计，95%的胰腺癌、35%的结直肠癌和25%的肺癌是由依赖于突变的 RAS-MAPK 信号传导。目前，针对这些大型疾病的治疗选择有限。患者人群。 KSR 的小分子靶向提供了一种调节 RAS 信号传导的新方法如果成功，可能会影响大量癌症患者。