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Therapeutic Targeting Mitochondrial C1 Metabolism

靶向线粒体 C1 代谢的治疗

基本信息

批准号：
10323292
负责人：
Charles E. Dann
金额：
$ 60.22万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10323292
关键词：
Acute Anabolism Antineoplastic Agents Biological Assay Cancer cell line Carbon Cell membrane Cells Characteristics Clinical Trials Collaborations Colon Colorectal Cancer Coupled Cytosol Development Disease Disease remission Dose Drug Delivery Systems Drug Kinetics Drug Metabolism Inhibition Drug Transport Enzymes Epithelial Epithelial Cells Epithelial ovarian cancer Equilibrium Evaluation Exhibits FDA approved FRAP1 gene Genetically Engineered Mouse Glutathione Glycine Glycine Hydroxymethyltransferase Human Hydroxymethyltransferases Hypoxia Immune In Vitro In complete remission KPC model KRAS2 gene Lead Malignant Neoplasms Malignant neoplasm of pancreas Measures Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Non-Small-Cell Lung Carcinoma Nucleotide Biosynthesis Nutrient Oxidation-Reduction Pancreas Partial Remission Pathway interactions Pemetrexed Pharmaceutical Chemistry Pharmacology Pharmacy (field)Prognostic Factor Protons Purines Pyrimidine Reactive Oxygen Species Recovery Regulation Research Respiration Ribonucleotides Role SLC19A1 gene Series Serine Signal Transduction Source Structure Survivors Testing Toxic effect Transplantation X-Ray Crystallography Xenograft Model Xenograft procedure advanced disease analog antitumor agent base cancer care cancer cell clinical care clinically relevant drug discovery efficacy trial gemcitabine glycine amide in vivo in vivo evaluation inhibitor lead optimization metabolomics mouse model mutant nanomolar new therapeutic target novel novel strategies pancreatic cancer cells pancreatic cancer model pancreatic cancer patients patient derived xenograft model preclinical study prototype standard of care structural biology therapeutic target thymidylate tumor tumor growth uptake

项目摘要

ABSTRACT Metabolic reprogramming is an important hallmark of cancer. Of the altered metabolic pathways associated with malignancy, one-carbon (C1) metabolism is particularly notable. The 3-carbon of serine is the major C1 donor for de novo synthesis of purines and thymidylate in the cytosol, and the primary catabolic pathway for serine and synthesis of glycine occurs in the mitochondria. The mitochondrial C1 pathway also generates reducing equivalents and is an important source of ATP. The first enzyme of the mitochondrial C1 pathway, serine hydroxymethyltransferase (SHMT) 2, is an oncodriver which is upregulated in a substantial number of cancers. Growing evidence suggests that SHMT2 could be an independent prognostic factor and an important therapeutic target for cancer. We discovered novel 5-substituted pyrrolo[3,2-d]pyrimidine compounds AGF291, AGF347, and AGF359. Following their internalization by the proton-coupled folate transporter (PCFT), these compounds inhibit mitochondrial C1 metabolism at SHMT2, with direct secondary inhibitions of cytosolic targets in de novo purine (DNP) biosynthesis (at 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase) and SHMT1. Our compounds inhibit proliferation of epithelial ovarian cancer, non-small cell lung cancer, colorectal cancer, and pancreatic cancer (PaC) cells, suggesting their potential as broad-spectrum anti-tumor agents. AGF347 exhibited significant in vivo antitumor efficacy with potential for complete responses against both early and upstage PaC xenograft models. We posit that our novel compounds offer an entirely new approach for treating cancer. Our objective is to optimize our lead structures for tumor targeting via PCFT and inhibition of mitochondrial and cytosolic C1 metabolism at modest doses with minimal toxicity. We will use PaC as a disease prototype for further development of our novel multi-targeted inhibitors. In Aim 1, we will synthesize up to 100 compounds based on lead compounds to optimize uptake by tumors, and inhibition of SHMT2 and cytosolic pathways including DNP biosynthesis. In Aim 2, we will test analogs from Aim 1 for antitumor potencies toward clinically relevant PaC cell lines, tumor selectivity and plasma membrane and mitochondrial drug transport, drug metabolism, and inhibition of SHMT2 and cytosolic pathways including DNP biosynthesis. We will measure downstream impacts on mTOR signaling, mitochondrial respiration, glutathione pools, and reactive oxygen species. In Aim 3, we will evaluate pharmacokinetics, tolerability, and in vivo antitumor activities of compounds from Aims 1 and 2 by toxicity/efficacy trials with human PaC cell line xenograft and PDX models, and with the KPC mouse PaC model. Our lead analogs are “first-in-class” and our proposed studies will afford optimized compounds with the best balance of selective tumor targeting and anti-tumor efficacy, resulting from inhibition of SHMT2 and downstream anabolic pathways. We anticipate developing SHMT2/DNP-targeted compounds for IND submission and clinical trials based on our studies.

抽象的代谢重编程是癌症的重要标志。相关代谢途径的改变对于恶性肿瘤，一碳 (C1) 代谢尤其值得注意。丝氨酸的3-碳是主要的C1 细胞质中嘌呤和胸苷酸从头合成的供体，以及主要分解代谢途径丝氨酸和甘氨酸的合成发生在线粒体中。线粒体 C1 途径还产生还原当量，是 ATP 的重要来源。线粒体C1途径的第一个酶，丝氨酸羟甲基转移酶 (SHMT) 2 是一种肿瘤驱动因子，在大量细胞中上调癌症。越来越多的证据表明 SHMT2 可能是一个独立的预后因素和重要的预后因素癌症的治疗靶点。我们发现了新型5-取代吡咯并[3,2-d]嘧啶化合物AGF291， AGF347 和 AGF359。在被质子耦合叶酸转运蛋白 (PCFT) 内化后，这些化合物抑制 SHMT2 处的线粒体 C1 代谢，并直接二级抑制胞质从头嘌呤 (DNP) 生物合成的靶点（5-氨基咪唑-4-甲酰胺核糖核苷酸）甲酰基转移酶和甘氨酰胺核糖核苷酸甲酰基转移酶）和 SHMT1。我们的化合物抑制上皮性卵巢癌、非小细胞肺癌、结直肠癌和胰腺癌的增殖（PaC）细胞，表明它们作为广谱抗肿瘤剂的潜力。 AGF347 表现出显着的体内抗肿瘤功效，对早期和后期 PaC 异种移植物具有完全反应的潜力模型。我们认为我们的新型化合物提供了一种治疗癌症的全新方法。我们的目标是通过 PCFT 和抑制线粒体和胞质来优化我们的肿瘤靶向先导结构 C1 代谢在适度剂量下具有最小的毒性。我们将使用 PaC 作为疾病原型进行进一步的研究开发我们的新型多靶点抑制剂。在目标 1 中，我们将合成多达 100 种基于对先导化合物进行优化以优化肿瘤的摄取，并抑制 SHMT2 和胞质途径，包括 DNP生物合成。在目标 2 中，我们将测试目标 1 的类似物的临床相关抗肿瘤效力 PaC 细胞系、肿瘤选择性以及质膜和线粒体药物转运、药物代谢和抑制 SHMT2 和胞质途径，包括 DNP 生物合成。我们将衡量下游影响 mTOR 信号传导、线粒体呼吸、谷胱甘肽池和活性氧。在目标 3 中，我们将通过以下方式评估目标 1 和 2 化合物的药代动力学、耐受性和体内抗肿瘤活性使用人类 PaC 细胞系异种移植物和 PDX 模型以及 KPC 小鼠 PaC 模型进行毒性/功效试验。我们的先导类似物是“一流的”，我们提出的研究将提供具有最佳性能的优化化合物通过抑制 SHMT2 和抑制选择性肿瘤靶向和抗肿瘤功效的平衡下游合成代谢途径。我们预计开发用于 IND 的 SHMT2/DNP 靶向化合物基于我们的研究的提交和临床试验。