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

• 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
• 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

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的激酶抑制因子(KSR)是一种丝裂原激活的蛋白激酶(MAPK)支架，受 通过与RAF的二聚化调节变构。在模型生物中的研究表明，直接靶向 KSR可能对癌症治疗有重要的治疗意义；然而，通过 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希望的先导化合物，它们直接与KSR结合以拮抗 致癌的RAS-MAPK信号转导(Dhawan等人，《自然》，2016)。这类独特的小分子， 通过稳定KSR失活状态(KSRi)发挥作用，通过阻碍Ras-MAPK信号转导而拮抗 RAF-KSR异二聚化和激活RAS效应蛋白激酶所需的构象变化 我是说。此外，我们还发现，KSRi具有提高现有药物疗效的潜力 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抑制剂在治疗RAS突变癌症患者中的应用。我们的初步研究 基于体外研究，包括重建分析、细胞系研究和结晶学。 分析。在这个提议中，我们以我们早期的线索为基础，创造出新的化学探针，这将是 适用于活体实验。从这项工作中产生的化合物将是 研究RAS-MAPK的机制、靶点和治疗方法。 此外，我们将研究直接靶向KSR作为一种抑制解除管制的RAS-MAPK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。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 Ras-MAPK通路在患者体内的表达被认为是癌症发生、发展、 转移，而且往往对靶向治疗产生抗药性。某些癌症亚型显示出高比例的 RAS基因突变；据估计，95%的胰腺癌、35%的结直肠癌和25%的肺癌是 依赖于突变的Ras-MAPK信号。目前，对于这些大型肿瘤的治疗选择有限。 患者群体。小分子靶向KSR为调节RAS信号提供了一种新途径 疾病的路径，如果成功，可能会影响大量的癌症患者。