Selectively Targeting Oncogenic NRAS in Cancer

选择性靶向癌症中的致癌 NRAS

• 批准号: 10610346
• 负责人: KEVIN M. SHANNON
• 金额: $ 50.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610346
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Alleles; Antineoplastic Agents; Biochemical; Biochemistry; Biological Availability; Biological Models; Biology; CRISPR interference; Cancer Cell Growth; Cell Line; Cell membrane; Cells; Chemical Actions; Chemicals; Co-Immunoprecipitations; Collaborations; Complex; Cysteine; Data; Development; Drug Targeting; Enzymes; Exhibits; Family; Funding; GOLGA7 gene; Genotype; Goals; Growth; Hematologic Neoplasms; Human; Individual; Knock-in Mouse; Knowledge; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Myelogenous; NRAS gene; Normal tissue morphology; Oncogenic; Output; Pathway interactions; Pre-Clinical Model; Production; Property; Protein Isoforms; Proteins; RAS driven cancer; RAS genes; RAS inhibition; Ras Inhibitor; Reaction; Research Personnel; Role; Serine Hydrolase; Signal Transduction; Testing; Therapeutic; Transferase; Xenograft procedure; acute myeloid leukemia cell; cancer cell; candidate validation; conditional mutant; drug development; drug discovery; experimental study; in vivo; inhibitor; innovation; leukemia; mutant; novel; novel strategies; novel therapeutic intervention; palmitoylation; pre-clinical; ras GTPase-Activating Proteins; ras Proteins; targeted agent; targeted treatment; therapeutic target; trafficking; transcriptome

SPECIFIC AIMS Oncogenic RAS mutations, which are among the most common molecular alterations in cancer, encode mutant proteins that dominantly drive aberrant growth. Unfortunately, structural and biochemical properties of the mutant Ras/GTPase activating protein (Ras/GAP) molecular switch pose formidable barriers to mechanism-based drug discovery and no targeted therapies have been approved for Ras-driven cancers to date. The Ras palmitoylation/depalmitoylation cycle regulates the subcellular trafficking of the N-Ras, H-Ras, and K-Ras4a isoforms, but not of K-Ras4b. Thus, developing potent and selective inhibitors of the Ras palmitoylation/depalmitoylation cycle has the potential to treat malignancies dependent on oncogenic N-Ras without interfering with K-Ras4b signaling in normal tissues. This ongoing project involves a cross-disciplinary collaboration between investigators with complementery expertise in biochemistry, chemical biology, hematologic cancer, Ras signaling, and preclinical therapeutics. During the current funding period we: (1) validated N-Ras palmitoylation as a promising therapeutic target for NRAS mutant cancers in a novel strain of NrasG12D,C181S “knock in” mice; (2) identified the ABHD17 family of serine hydrolase (SH) enzymes as N-Ras depalmitoylases; (3) showed that the Palmostatin class of SH inhibitors are too promiscuous for use as selective probes of ABHD17 function; (4) identified, in collaboration with Lundbeck, a structurally distinct class of selective ABHD17 inhibitors that reduce the growth of NRAS mutant acute myeloid leukemia (AML) cells and exhibit genotype-specific activity in isogenic models; and, (5) demonstrated that reduced growth of NRAS mutant AML cells treated with ABHD17 inhibigtors correlates with biochemical inhibition of Ras effector pathways. The experiments proposed in this renewal application will extend these exciting studies through the following specific aims: Aim 1. To investigate the roles of ABHD17s and additional SH enzymes in N-Ras depalmitoylation and to test the potent and bioavailable ABHD17 inhibitor ABD778 in preclinical models of AML; and, Aim 2. To identify palmitoyl acyl transferase (PAT) proteins that modify N-Ras and to validate them as targets for N-Ras mutant cancers. We anticipate that the studies described in this interdisciplinary project will determine fundamental mechanisms of N-Ras palmitoylation, ascertain the efficacy and mechanism of action of chemical inhibitors of ABHD17s alone and in combination with other targeted agents, and generate essential foundational knowledge for developing PAT inhibitors as anti-cancer drugs. The development of selective inhibitors of oncogenic N-Ras signaling would have significant therapeutic impact for a number of different aggressive adult and pediatric cancers.

具体目标 致癌RAS突变是癌症中最常见的分子变化之一，它编码 主要驱动异常生长的突变蛋白质。不幸的是，它的结构和生化特性 突变的RAS/GTP酶激活蛋白(RAS/GAP)分子开关对 基于机制的药物发现和没有靶向治疗已经被批准用于RAS驱动的癌症 约会。RAS棕榈酰化/去醛化循环调节N-RAS，H-RAS， K-Ras4a亚型，而不是K-Ras4b亚型。因此，开发有效和选择性的RAS抑制剂 棕榈酰化/脱氨酰化循环有可能治疗依赖致癌N-RAS的恶性肿瘤 而不干扰正常组织中的K-Ras4b信号。这个正在进行的项目涉及一个跨学科的 在生物化学、化学生物学、 血液学癌症、RAS信号转导和临床前治疗。在本资助期内，我们：(1) N-RAS棕榈酰化是一种新的NRAS突变癌症的有效治疗靶点 NrasG12D，C181S敲入小鼠；(2)鉴定ABHD17丝氨酸水解酶家族为N-RAS 去almitoylase；(3)显示Palmostatin类SH抑制剂太过混杂，不能用作 ABHD17功能的选择性探针；(4)与伦德贝克合作，确定了一个结构上不同的类别 抑制NRAS突变型急性髓系白血病(AML)细胞生长的选择性ABHD17抑制剂 并在等基因模型中表现出特定的基因活性；以及，(5)表明NRAS的生长减少 ABHD17抑制剂处理突变型AML细胞与RAS效应的生化抑制相关 小路。在这个续订申请中提出的实验将通过 目的1.研究ABHD17s和附加的SH酶在N-RAS中的作用 并在临床前模型中测试ABHD17抑制剂ABD778的有效性和生物利用度。 目的2.鉴定修饰N-RAS的棕榈酰转移酶(PAT)蛋白并对其进行验证 作为N-RAS突变癌症的靶点。我们预计这个跨学科项目中描述的研究 将确定N-RAS棕榈酰化的基本机制，确定其疗效和机制 ABHD17的化学抑制剂单独或与其他靶向药物联合作用，并产生 开发PAT抑制剂作为抗癌药物的基本基础知识。的发展。 致癌N-RAS信号的选择性抑制剂将对一些 不同的侵袭性成人和儿童癌症。