Targeting Oncogenic Ras-MAPK Signaling Complexes via the Scaffold KSR

RAS激酶抑制因子（KSR）是一种丝裂原活化蛋白激酶（MAPK）支架， 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 由于缺乏KSR功能的小分子拮抗剂，药理学方法一直是困难的。 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， 致癌RAS-MAPK信号传导（Dhawan等人，Nature，2016）。这种独特的小分子， 通过稳定KSR失活状态（KSRi）起作用，通过阻碍RAS-MAPK信号传导来拮抗RAS-MAPK信号传导， RAF-KSR异源二聚化和RAS效应激酶激活所需的构象变化 MEK.此外，我们已经发现KSRi具有增加目前可用的药物的功效的潜力。 MAPK抑制剂（包括MEK抑制剂）通过增加治疗指数，从而扩大潜力 目前可用的MAPK抑制剂治疗RAS突变型癌症患者的效用。我们的初步研究 已经基于体外研究，包括重建测定、细胞系研究和晶体学研究。 分析.在这个提议中，我们建立在我们早期的线索上，以创造新的化学探针， 适用于体内实验。从这项工作中产生的化合物将是有价值的工具， RAS-MAPK机制、靶点和治疗方法的研究。 此外，我们将研究直接靶向KSR作为抑制RAS-MAPK失调的机制 患者来源的和耐药癌症模型中的信号通路。RAS-MAPK通路是 在大约25%的人类癌症中激活，最常见的是通过K-RAS中的点突变。放松管制 RAS-MAPK途径的改变被认为是癌症发生、进展 转移，并且通常对靶向治疗有抗性。某些癌症亚型表现出高比例的 RAS突变;据估计，95%的胰腺癌、35%的结直肠癌和25%的肺癌是RAS突变。 依赖于突变的RAS-MAPK信号传导。目前，对于这些大的肿瘤，治疗选择有限。 患者人群。靶向KSR的小分子提供了一种调节RAS信号的新方法 如果成功，可能会影响大量癌症患者。

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.