Preclinical Development of First-in-Class NDUFS7 Antagonists for the Treatment of Pancreatic Cancer

用于治疗胰腺癌的一流 NDUFS7 拮抗剂的临床前开发

• 批准号: 10684845
• 负责人: NOURI NEAMATI
• 金额: $ 46.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684845
• 关键词: Ablation; Antimycin A; Bioenergetics; Biomass; Bromouridine sequencing; Cancer cell line; Cell Hypoxia; Cell Line; Cells; Clinical; Clinical Research; DNA Repair Gene; Data; Dependence; Disease; Dose; Down-Regulation; Drug Combinations; Drug Delivery Systems; Drug or chemical Tissue Distribution; Drug resistance; Equilibrium; FDA approved; Future; Generations; Genes; Genetically Engineered Mouse; Glycolysis; Growth; Human; Image; Immune checkpoint inhibitor; KRAS2 gene; Lead; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediating; Metformin; Mission; Mitochondria; Modeling; Mus; Mutate; Neoplasm Metastasis; Null Lymphocytes; Oligomycins; Oncology; Oral; Organ; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; PTEN gene; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Phosphorylation Inhibition; Play; Production; Prognosis; Proliferating; Proteomics; Public Health; Resistance; Role; Rotenone; SWI/SNF Family Complex; Safety; Series; Testing; Therapeutic; Toxic effect; Transgenic Mice; Tumor Tissue; Tumor-Associated Process; Tyrosine Kinase Inhibitor; United States National Institutes of Health; Work; analog; antagonist; cancer cell; cancer stem cell; chemotherapy; clinical candidate; clinical development; cohort; cytotoxicity; design; efficacy evaluation; exome sequencing; gemcitabine; in vivo; inhibitor; innovation; lead optimization; multiple omics; nanomolar; novel; novel therapeutics; overexpression; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; patient subsets; pharmacokinetics and pharmacodynamics; pharmacologic; preclinical development; response; standard of care; synergism; three dimensional cell culture; tool; transcriptome sequencing; tumor initiation; tumor progression

Oxidative phosphorylation (OXPHOS) plays an important role in mitochondria function by mediating bioenergetics, biomass production, and redox balance, all essential processes for tumor progression, metastasis, and survival. Thus, targeting OXPHOS holds great promise to treat PDAC. Metformin, a clinically used OXPHOS inhibitor, has demonstrated increased survival in PDAC patients, suggesting that OXPHOS inhibitors can safely be used to treat PDAC. A clearer picture is now emerging on the essential role of OXPHOS in PDAC progression. For example, overexpression of OXPHOS genes correlates with poor prognosis in PDAC patients, and suppression of mitochondrial oxygen consumption significantly retards PDAC progression. Drug resistant PDAC cells ablated in KRAS are heavily dependent on OXPHOS and are sensitive to OXPHOS inhibition. Pancreatic-tumor-initiating cells also show strong reliance on OXPHOS. Importantly, OXPHOS inhibitors are synergistic with gemcitabine specifically in cells with high levels of OXPHOS-related genes. Unfortunately, metformin has low potency and poor selectivity. Other classic OXPHOS inhibitors including rotenone, antimycin A, and oligomycin, lack selectivity. We recently designed a series of highly potent OXPHOS inhibitors (DX2-201 to DX3-236). Our ADMET-guided lead optimization campaign generated over 200 novel analogues that led to the discovery of orally active OXPHOS inhibitors with nanomolar potency, acceptable toxicity, and reasonable organ distributions to advance into clinical development. We profiled a set of 105 cancer cell lines for their anti-proliferative response to DX analogues and found that our compounds profoundly inhibit the proliferation of 5 out of 7 PDAC cell lines. Through the generation of drug resistance clones, followed by whole exome sequencing, we identified NDUFS7 as the direct target of our lead compound DX2-201 in 6/6 clones. Our integrated multi-omics (RNA-seq, Bru-seq and mass spectrometry-based proteomics) studies revealed down-regulation of DNA repair genes upon DX treatment. Our DX compounds also show significant synergism with standard-of-care chemotherapy and several FDA-approved drugs. We hypothesize that OXPHOS inhibitors will provide therapeutic benefit to PDAC patients, overcome drug resistance, and could be safely and efficaciously combined with various drugs including immune checkpoint inhibitors. We will test this hypothesis through the following specific aims: Aim 1. To assess cytotoxicity of top 5 compounds as single agent and in combination with standard chemotherapy as well as several early-stage clinical candidates in a large panel of mouse and human PDAC cell lines. Aim 2. To perform MTD, full PK/PD studies, and to determine tissue distribution and accumulation of top 5 compounds in mice. Aim 3. To determine the in vivo efficacy of top 5 compounds as single agents and in combination with standard-of-care drug(s) from Aim 1 in orthotopic and GEMM models of KRAS driven pancreatic cancer.

氧化磷酸化（OXPHOS）通过介导在线粒体功能中发挥重要作用 生物能学、生物量产生和氧化还原平衡，肿瘤进展的所有重要过程， 转移和生存。因此，靶向 OXPHOS 为治疗 PDAC 带来了巨大希望。二甲双胍，临床上 使用 OXPHOS 抑制剂，已证明 PDAC 患者的生存率增加，表明 OXPHOS 抑制剂可以安全地用于治疗 PDAC。现在人们对 OXPHOS 的重要作用有了更清晰的认识 在 PDAC 进展中。例如，OXPHOS 基因的过度表达与 PDAC 的不良预后相关 患者，抑制线粒体耗氧量可显着延缓 PDAC 进展。药品 KRAS 中消除的耐药 PDAC 细胞严重依赖 OXPHOS，并对 OXPHOS 敏感 抑制。胰腺肿瘤起始细胞也表现出对 OXPHOS 的强烈依赖。重要的是，OXPHOS 抑制剂与吉西他滨具有协同作用，特别是在具有高水平 OXPHOS 相关基因的细胞中。 不幸的是，二甲双胍效力低且选择性差。其他经典的 OXPHOS 抑制剂包括 鱼藤酮、抗霉素 A 和寡霉素缺乏选择性。我们最近设计了一系列高效的 OXPHOS 抑制剂（DX2-201 至 DX3-236）。我们的 ADMET 引导的先导化合物优化活动产生了 200 多个新颖的 导致发现具有纳摩尔效力的口服活性 OXPHOS 抑制剂的类似物，可接受 毒性和合理的器官分布，以推进临床开发。我们对 105 种癌症进行了分析 细胞系对 DX 类似物的抗增殖反应，发现我们的化合物可以深度抑制 7 个 PDAC 细胞系中有 5 个的增殖。通过产生耐药性克隆，然后 全外显子组测序，我们在 6/6 中确定 NDUFS7 是我们的先导化合物 DX2-201 的直接靶标 克隆。我们的综合多组学（RNA-seq、Bru-seq 和基于质谱的蛋白质组学）研究 揭示了 DX 处理后 DNA 修复基因的下调。我们的 DX 化合物也显示出显着的 与标准护理化疗和 FDA 批准的几种药物具有协同作用。我们假设 OXPHOS 抑制剂将为 PDAC 患者提供治疗益处，克服耐药性，并可能成为 安全有效地与包括免疫检查点抑制剂在内的多种药物联合使用。我们将测试这个 通过以下具体目标提出假设： 目标 1. 评估前 5 种化合物作为单一药物的细胞毒性 并与标准化疗以及大型临床试验中的几种早期临床候选药物相结合 小鼠和人类 PDAC 细胞系组。目标 2. 进行 MTD、完整的 PK/PD 研究并确定组织 前 5 种化合物在小鼠体内的分布和积累。目标 3. 确定前 5 种药物的体内功效 化合物作为单一药物并与目标 1 中的标准治疗药物组合用于原位和 KRAS 驱动的胰腺癌的 GEMM 模型。

项目成果

Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer.

• DOI: 10.1021/acs.jmedchem.2c01769
• 发表时间: 2023-01
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Joyeeta Roy;A. Kyani;Maha Hanafi;Yibin Xu;J. Takyi-Williams;Duxin Sun;E. E. A. Osman-E.;N. Neamati