Selectively Targeting Oncogenic NRAS in Cancer

选择性靶向癌症中的致癌 NRAS

• 批准号: 10372214
• 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/10372214
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Alleles; Antineoplastic Agents; Biochemical; Biochemistry; 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; Foundations; 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 genes; RAS inhibition; Ras Inhibitor; Reaction; Research Personnel; Role; Serine Hydrolase; Signal Transduction; Testing; Therapeutic; Transferase; Xenograft procedure; acute myeloid leukemia cell; base; cancer cell; 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 致癌性RAS突变是癌症中最常见的分子改变之一 突变蛋白主要驱动异常生长。不幸的是，结构和生化特性 突变的RAS/GTPase激活蛋白（RAS/GAP）分子开关构成强大的障碍 基于机制的药物发现和未针对RAS驱动的癌症批准了尚无靶向疗法 日期。 RAS棕榈酰化/去氨木酰化周期调节N-RAS，H-RAS的亚细胞运输 和K-RAS4A同工型，但不是K-RAS4B。那是RAS的潜力和选择性抑制剂 棕榈油/去氨木二酰化周期具有治疗依赖于致癌N-RAS的恶性肿瘤 不干扰正常组织中的K-RAS4B信号传导。这个正在进行的项目涉及跨学科 研究人员与完整的生物化学专业知识，化学生物学专业知识， 血液学癌，RAS信号传导和临床前治疗。在当前的资金期内我们：（1） 经过验证的N-RAS棕榈酰化是NRAS突变癌的有希望的治疗靶点 Nrasg12d，C181S“敲入”小鼠； （2）将ABHD17丝氨酸水解酶（SH）酶定为N-RAS 去山霉菌; （3）表明，最大的SH抑制剂类别太滥交了，无法用作 ABHD17功能的选择性问题； （4）与Lundbeck合作确定了一个结构上不同的类别 选择性ABHD17的抑制剂，这些抑制剂降低了NRAS突变体急性髓样白血病（AML）细胞的生长 以及在等生模型中暴露的基因型特异性活性； （5）证明了NRA的生长降低 用ABHD17抑制剂处理的突变AML细胞与RAS效应子的生化抑制相关 途径。在此续签应用中提出的实验将通过 以下特定目的：目标1。研究ABHD17的作用和N-RAS中的其他SH酶 在临床前模型中，去氨酰二酰化并测试潜在和可生物利用的ABHD17抑制剂ABD778 AML;以及目标2。确定修饰N-RAS并验证的棕榈酰酰基转移酶（PAT）蛋白 作为N-RAS突变癌的靶标。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 单独使用ABHD17的化学抑制剂并与其他靶向剂结合起来的作用，并产生 将PAT抑制剂作为抗癌药物开发的基本知识。发展的发展 致癌N-RAS信号传导的选择性抑制剂将对许多人产生重大的热影响 不同的侵略性成人和儿科取消者。