Selectively Targeting Oncogenic NRAS in Cancer

选择性靶向癌症中的致癌 NRAS

基本信息

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
项目类别：
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

项目摘要

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改变之一，编码不幸的是，主要驱动异常生长的突变蛋白的结构和生化特性。突变的 Ras/GTPase 激活蛋白 (Ras/GAP) 分子开关对基于机制的药物发现，并且尚未批准针对 Ras 驱动的癌症的靶向治疗 Ras 棕榈酰化/去棕榈酰化循环调节 N-Ras、H-Ras、和 K-Ras4a 亚型，但不是 K-Ras4b 亚型，因此，开发有效的选择性 Ras 抑制剂。棕榈酰化/去棕榈酰化循环具有治疗依赖于致癌 N-Ras 的恶性肿瘤的潜力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。具有生物化学、化学生物学、血液癌症、Ras 信号转导和临床前治疗在当前资助期间我们：(1) 验证了 N-Ras 棕榈酰化作为一种新型菌株中 NRAS 突变癌症的有前景的治疗靶点 NrasG12D、C181S“敲入”小鼠；(2) 鉴定出 ABHD17 丝氨酸水解酶 (SH) 家族为 N-Ras 去棕榈酰酶；(3) 表明棕榈抑素类 SH 抑制剂过于混杂，不适合用作 ABHD17 功能的选择性探针；(4) 与 Lundbeck 合作，鉴定出一个结构独特的类别选择性 ABHD17 抑制剂可减少 NRAS 突变急性髓系白血病 (AML) 细胞的生长并在同基因模型中表现出基因型特异性活性；并且，(5) 证明 NRAS 的生长减少用 ABHD17 抑制剂处理的突变 AML 细胞与 Ras 效应子的生化抑制相关该更新申请中提出的实验将通过以下方式扩展这些令人兴奋的研究。以下具体目标：目标 1. 研究 ABHD17s 和其他 SH 酶在 N-Ras 中的作用去棕榈酰化并在临床前模型中测试有效且具有生物利用度的 ABHD17 抑制剂 ABD778 AML；目标 2. 鉴定修饰 N-Ras 的棕榈酰酰基转移酶 (PAT) 蛋白并对其进行验证作为 N-Ras 突变癌症的靶标，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，确定其功效和机制 ABHD17s 化学抑制剂单独作用以及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重要基础知识。致癌 N-Ras 信号传导的选择性抑制剂将对许多癌症产生显着的治疗影响不同的侵袭性成人和儿童癌症。