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 GTP 酶 Ras 是所有癌症中最常见突变的癌基因之一 (20-30%)。 Ras 家族成员（K-Ras、H-Ras 和 N-Ras）调节多种生物过程，例如发育、生长和蛋白质翻译。 Ras 失调从根本上促进肿瘤的发生、转移过程和化疗耐药性的发展。到目前为止，Ras 致癌基因已经抑制了直接的药理学方法，而 Ras 直接效应物的抑制剂已证明对患者疗效有限或无效。基因筛选发现 Ras 激酶抑制因子 (KSR) 的点突变是致癌 Ras 的有效抑制因子，这表明 KSR 可以产生针对 Ras 的靶向干预的新方法。尽管 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节模式尚未实用。 KSR 属于蛋白激酶的一个亚类，称为假激酶，其天然无活性，因此不符合传统的激酶抑制剂策略。在最近的研究中，我们发现 KSR 是一种独特的信号分子，它充当 Ras 通路的动态支架（Brennan 和 Dar 等人，Nature，2011）。在一种状态下，KSR 充当 Ras 效应器 MEK 的抑制剂。在另一种状态下，KSR 是 Ras 下游激酶（称为 RAF）MEK 磷酸化的促进剂。 KSR 中的单点突变可抑制致癌 Ras 的转化，解开 KSR 两种状态之间的转变，并提出通过 KSR 实现 Ras 化学抑制剂的新途径。使用基于结构的策略，我们将生成小分子来调节 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（包括基于工程的细胞和基因定义的癌症模型）中表征这些分子，从而表征 KSR 的构象状态。此外，我们将把我们的目标化学和分析与整个动物分析和果蝇遗传学结合起来。我们最近应用这一策略来开发针对 Ret 激酶驱动的癌症的新疗法（Dar 和 Das 等人，Nature，2012）。在这里，我们将在此成功的基础上确定稳定 KSR 的 Ras 抑制构象的分子，作为 Ras 依赖性癌症的新疗法。总之，这种方法将揭示假激酶 KSR 的药物靶向与整个癌症动物模型中的系统范围反应之间的功能关系。如果成功，这种方法将极大地扩大药物开发的机会，揭示与激酶磷酸化活性无关的调节功能和控制机制，并培育一种针对癌症、糖尿病和心脏病等疾病中的非活性激酶的新范例。