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）通过介导线粒体的功能， 生物能量学、生物量产生和氧化还原平衡，所有肿瘤进展的基本过程， 转移和存活。因此，靶向OXPHOS具有治疗PDAC的巨大希望。Metabolism，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，对OXPHOS的重要作用有了更清楚的认识 PDAC进展。例如，OXPHOS基因的过表达与PDAC的不良预后相关， 患者，并且抑制线粒体氧消耗显著延缓PDAC进展。药物 在KRAS中消融的耐药PDAC细胞严重依赖于OXPHOS，并且对OXPHOS敏感 抑制作用胰腺肿瘤起始细胞也显示出对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，二甲双胍的效力低，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（DX 2 -201至DX 3 -236）。我们的ADMET引导的潜在客户优化活动产生了200多个新的 导致发现具有纳摩尔效力的口服活性OXPHOS抑制剂的类似物， 毒性和合理的器官分布，以推进临床开发。我们分析了一组105个癌症 细胞系对DX类似物的抗增殖反应，发现我们的化合物深刻地抑制了 7个PDAC细胞系中有5个细胞增殖。通过产生抗药性克隆， 通过全外显子组测序，我们在6/6中将NDUFS 7鉴定为我们的先导化合物DX 2 -201的直接靶点。 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治疗后DNA修复基因的下调。我们的DX化合物还显示出显著的 与标准化疗和几种FDA批准的药物协同作用。我们假设 OXPHOS抑制剂将为PDAC患者提供治疗益处，克服耐药性，并且可以用于 安全有效地与包括免疫检查点抑制剂在内的各种药物联用。我们将测试这个 假设通过以下具体目标：目标1。评估前5种化合物作为单药的细胞毒性 并与标准化疗以及几种早期临床候选药物联合使用， 一组小鼠和人PDAC细胞系。目标2.进行MTD、完整PK/PD研究，并测定组织 前5种化合物在小鼠体内的分布和蓄积。目标3.确定前5名的体内功效 作为单一药剂的化合物和与来自目标1的标准护理药物的组合， 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