Targeted Depalmitoylation for the Treatment of NRas-Driven Melanoma

靶向去棕榈酰化治疗 NRas 驱动的黑色素瘤

• 批准号: 10415478
• 负责人: Neal Krishna Devaraj
• 金额: $ 6.15万
• 依托单位: PALM THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415478
• 关键词: Address; Administrative Supplement; Aftercare; American; Aminophenols; Apoptosis; Behavior; Binding; Biological Assay; Biology; C-terminal; Cell Death; Cell Line; Cell Survival; Cell membrane; Cells; Chemicals; Chemistry; Collection; Complementarity Determining Regions; Coupling; Data; Development; Diagnosis; Disease; Dose; Drug Kinetics; Drug Targeting; Economic Burden; Evaluation; Exhibits; Foundations; Generations; Goals; Growth; Health; Human Cell Line; Hydrophobicity; In Vitro; Intravenous; Joints; Lead; Lipids; Malignant Neoplasms; Mammalian Cell; Maximum Tolerated Dose; Measures; Melanoma Cell; Metastatic Melanoma; Mission; Modeling; Monomeric GTP-Binding Proteins; Mutation; Oncogenic; Oncology; Operative Surgical Procedures; Oral; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plant Resins; Preclinical Testing; Proteins; Ras Signaling Pathway; Research Personnel; Route; Signal Induction; Signal Transduction; Skin Cancer; Small Business Innovation Research Grant; Structure; Surface; Tail; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Work; Xenograft procedure; base; commercialization; drug development; effective therapy; efficacy evaluation; improved; in vivo; in vivo evaluation; inhibitor; innovation; interest; intraperitoneal; leukemia/lymphoma; lipophilicity; melanoma; mouse model; mutant; neglect; novel; palmitoylation; preclinical evaluation; preclinical study; prevent; response; scaffold; screening; small molecule; small molecule inhibitor; targeted cancer therapy; targeted treatment; therapeutic target; thioester

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-20-012. Significance: Melanoma is the deadliest form of skin cancer and represents a growing economic burden and health concern in the U.S. While early-stage melanoma can often be treated surgically, therapies for advanced forms of the disease are severely lacking. As rates of melanoma continue to rise, it is imperative that we develop novel and effective treatments for this disease. The most aggressive form of melanoma results from a mutation in the small GTPase NRas and presents in 20% of patients. While NRas is an attractive therapeutic target in melanoma, it has proven notoriously difficult to drug due to the lack of suitable binding pockets on its surface. This limitation has prevented the development of NRas-targeted therapies. Objective: To address the unmet need for NRas- targeted drugs, we will target a previously overlooked region of NRas, the S-palmitoylation of its C-terminal hypervariable region. Numerous studies have confirmed that NRas palmitoylation is required for its cancer signaling activity. To exploit this feature of NRas, we have developed a novel class of Depalmitoylating Molecules (DPALMs) which chemoselectively cleave S-palmitoyl groups from proteins in live cells. Preliminary Data: We have identified a set of DPALM lead compounds which preferentially depalmitoylate NRas in living cells. Furthermore, we found that DPALMs can inhibit downstream Ras signaling pathways and preferentially kill NRas-mutant versus non-NRas-mutant cell lines, highlighting their therapeutic potential. Specific Aims: We will optimize the potency and selectivity of our lead compounds to generate a DPALM suitable for preclinical testing and IND enabling studies. In SPECIFIC AIM 1, we will generate a set of optimized DPALMs using joint synthesis and screening efforts. A modular and robust synthetic strategy will be used to generate new compounds which will then be screened for NRas depalmitoylation activity and selectivity in a validated assay. In SPECIFIC AIM 2, we will evaluate the efficacy of optimized DPALMs in NRas-driven melanoma cell lines. Compounds will be tested for their ability to preferentially inhibit growth and induce cell death in NRas-driven versus control cell lines. In SPECIFIC AIM 3, we will evaluate the in vivo toxicity, pharmacokinetics, and antitumor activity of the newly optimized DPALM-45. The proposed studies will enable the development of a highly NRas-selective DPALM and accelerate the commercialization of this targeted therapy for the treatment of melanoma and several other cancers with high rates of NRas-mutations.

项目摘要 该申请是为了响应特殊利益通知（NOSI）而提交 非CA-20-012。 意义： 黑色素瘤是皮肤癌最致命的形式，代表了日益严重的经济负担和健康问题 在美国，虽然早期黑色素瘤通常可以手术治疗，但对先进形式的疗法 疾病严重缺乏。随着黑色素瘤的速度继续上升，我们必须发展新颖和 有效治疗这种疾病。黑色素瘤最具侵略性的形式是由小突变引起的 GTPase NRA和20％的患者呈现。而NRA是黑色素瘤中有吸引力的治疗靶标的 由于表面缺乏合适的结合口袋，因此被证明很难吸毒。这个限制 已经阻止了NRAS靶向疗法的发展。目的：满足未满足的NRAS- 有针对性的药物，我们将针对先前被忽视的NRA的区域 高变量区域。大量研究证实，其癌症需要NRAS棕榈酰化 信号活动。为了利用NRA的这一特征，我们已经开发了一类新型的deplitoyplating分子 （DPALMS）从活细胞中的蛋白质裂解S-膜酰基的化学选择性。初步数据：我们 已经鉴定出一组DPALM铅化合物，这些化合物优先在活细胞中depalmitoylate NRA。 此外，我们发现DPALM可以抑制下游RAS信号通路并优先杀死 NRAS突变和非NRAS突变细胞系，突出了其治疗潜力。具体目的：我们将 优化铅化合物的效力和选择性，以生成适合临床前测试的DPALM 和IND促进研究。在特定目标1中，我们将使用关节合成生成一组优化的DPALM 和筛查工作。模块化稳健的合成策略将用于生成新化合物 然后将在经过验证的测定中筛选NRAS depalmitoylation活性和选择性。在特定目标中 2，我们将评估优化DPALM在NRAS驱动的黑色素瘤细胞系中的疗效。化合物将是 测试了它们优先抑制生长并诱导NRAS驱动与对照细胞中细胞死亡的能力 线。在特定目标3中，我们将评估体内毒性，药代动力学和抗肿瘤活性 新优化的DPALM-45。拟议的研究将使高度NRAS选择性的发展 DPALM并加速了该靶向疗法用于治疗黑色素瘤的商业化和几种 其他NRAS突变率很高的癌症。