Targeting Ras-Dependent Cancers with a Chemical Switch for an Inactive Kinase

通过针对非活性激酶的化学​​开关靶向 Ras 依赖性癌症

• 批准号: 8572670
• 负责人: Arvin Dar
• 金额: $ 254.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8572670
• 关键词: Animal Cancer Model; Animals; Biological Assay; Biological Process; Cancer Model; Chemicals; Chemistry; Development; Diabetes Mellitus; Disease; Drug Targeting; Family; Family member; Fostering; Genetic; Genetic Screening; Growth and Development function; HRAS gene; Heart Diseases; Intervention; MEKs; Malignant Neoplasms; Molecular Conformation; Monomeric GTP-Binding Proteins; Mutate; Mutation; Nature; Oncogenes; Oncogenic; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Point Mutation; Protein Kinase; Proteins; Ras Inhibitor; Regulation; Signaling Molecule; Structure; System; Translating; Translations; base; cellular engineering; complex biological systems; drug development; fly; human KSR protein; inhibitor/antagonist; kinase inhibitor; member; metastatic process; novel; novel strategies; novel therapeutics; ras Oncogene; response; scaffold; small molecule; success; tumor initiation

DESCRIPTION (provided by applicant): The small GTPase, Ras, is one of the most frequently mutated oncogenes (20-30%) across all cancers. Ras family members (K-Ras, H-Ras, and N-Ras) regulate diverse biological processes, such as development, growth and protein translation. Dysregulation of Ras contributes fundamentally to the initiation of tumors, the metastatic process and the development of chemoresistance. To this point, Ras oncogenes have stifled direct pharmacological approaches, and inhibitors for the direct effectors of Ras have demonstrated limited or no efficacy within patients. Genetic screens identified point mutations in Kinase Suppressor of Ras (KSR) as potent suppressors of oncogenic Ras, suggesting that KSR could yield novel approaches for Ras-targeted interventions. Although KSR is a member of the protein kinase family, translating KSR mutations into a viable mode of chemical regulation has not yet been practical. KSR belongs to a subclass of protein kinases, termed pseudokinases, which are naturally inactive and therefore belie conventional kinase inhibitor strategies. In recent studies, we identified KSR as a distinct signaling molecule, which functions as a dynamic scaffold of the Ras pathway (Brennan and Dar et al., Nature, 2011). In one state, KSR behaves as an inhibitor of the Ras effector MEK. In another state, KSR is a facilitator of MEK phosphorylation by the kinase immediately downstream of Ras termed RAF. Single point mutations in KSR, which suppress transformation by oncogenic Ras, uncouple the transition between the two states of KSR and suggest novel paths to a chemical suppressor of Ras via KSR. Using structure-based strategies, we will generate small molecules to modulate KSR so that we may stabilize it in distinct conformational states. We aim to characterize these molecules, and thus the conformational states of KSR, within complex biological systems including engineered cell-based and genetically defined cancer models. Additionally, we will combine our target focused chemistry and profiling with whole animal assays and genetics in the fly. We recently applied this strategy to develop novel therapeutics for Ret-kinase driven cancers (Dar and Das et al., Nature, 2012). Here we will build upon this success to identify molecules that stabilize the Ras-suppressive conformation of KSR as novel treatments for Ras-dependent cancers. Together, this approach will reveal the functional relationship between drug targeting of the pseudokinase KSR and system wide responses within whole animal models of cancer. If successful, this approach will greatly expand opportunities for drug development, reveal regulatory functions and control mechanisms that appear independent of kinase phosphorylation activity, and foster a new paradigm of targeting inactive kinases in diseases including cancer, diabetes, and heart disease.

描述（由申请人提供）：小GT3，Ras，是所有癌症中最常见的突变癌基因之一（20-30%）。Ras家族成员（K-Ras、H-Ras和N-Ras）调节多种生物过程，如发育、生长和蛋白质翻译。Ras的失调从根本上有助于肿瘤的发生、转移过程和化学抗性的发展。在这一点上，Ras癌基因已经抑制了直接的药理学方法，并且Ras的直接效应物的抑制剂在患者中表现出有限的功效或没有功效。基因筛选将Ras激酶抑制因子（KSR）中的点突变确定为致癌Ras的有效抑制因子，这表明KSR可以产生Ras靶向干预的新方法。虽然KSR是蛋白激酶家族的一员，但将KSR突变转化为可行的化学调控模式尚未实现。KSR属于蛋白激酶的一个亚类，称为假激酶，其天然无活性，因此与常规激酶抑制剂策略不同。在最近的研究中，我们将KSR鉴定为独特的信号传导分子，其作为Ras途径的动态支架发挥作用（Brennan和Dar等人，Nature，2011）。在一种状态下，KSR表现为Ras效应物MEK的抑制剂。在另一种状态下，KSR是Ras下游激酶（称为RAF）对MEK磷酸化的促进剂。KSR中的单点突变抑制致癌Ras的转化，使KSR的两种状态之间的转换解偶联，并通过KSR提出了Ras化学抑制剂的新途径。使用基于结构的策略，我们将产生小分子来调节KSR，以便我们可以将其稳定在不同的构象状态。我们的目标是在复杂的生物系统，包括工程细胞为基础的和遗传定义的癌症模型中表征这些分子，从而确定KSR的构象状态。此外，我们将联合收割机结合我们的目标集中的化学和分析与整个动物的测定和遗传学的飞行。我们最近应用该策略来开发用于Ret-kinase驱动的癌症的新疗法（Dar and Das et al.，Nature，2012）。在这里，我们将建立在这一成功的基础上，以确定分子，稳定Ras抑制构象的KSR作为新的治疗Ras依赖性癌症。总之，这种方法将揭示假激酶KSR的药物靶向和癌症的整个动物模型内的系统范围的响应之间的功能关系。如果成功，这种方法将大大扩大药物开发的机会，揭示独立于激酶磷酸化活性的调节功能和控制机制，并促进靶向癌症，糖尿病和心脏病等疾病中的非活性激酶的新范式。