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。与改变的代谢途径相关的由于恶性肿瘤，一碳（C1）代谢特别值得注意。丝氨酸的3碳是主要的C1 从头合成王子和胸甲酯中的供体在细胞质中的供体，以及主要的分解代谢途径甘氨酸的丝氨酸和合成发生在线粒体中。线粒体C1途径也会生成减少等效物，是ATP的重要来源。线粒体C1途径的第一种酶，丝氨酸羟甲基转移酶（SHMT）2是一种oncodriver，以大量数量进行更新癌症。越来越多的证据表明，SHMT2可能是一个独立的预后因素，并且是重要的癌症的治疗靶标。我们发现了新型的5二取代吡咯[3,2-D]嘧啶化合物Agf291， AGF347和AGF359。遵循质子耦合叶酸转运蛋白（PCFT）的内在化，这些化合物在SHMT2处抑制线粒体C1代谢，直接二次抑制胞质从头购买（DNP）生物合成的靶标（在5-氨基咪唑-4-羧酰胺核糖核苷酸甲基转移酶和糖酰胺核糖核苷酸甲基转移酶）和SHMT1。我们的化合物抑制上皮卵巢癌，非小细胞肺癌，有色癌和胰腺癌的扩散（PAC）细胞，表明它们作为广谱抗肿瘤剂的潜力。 AGF347暴露于体内抗肿瘤效率具有针对早期和上台PAC异种移植的完全反应的潜力型号。我们认为我们的新颖化合物为治疗癌症提供了一种全新的方法。我们的目标是通过PCFT和抑制线粒体和胞质的抑制量靶向肿瘤的铅结构 C1代谢的适度剂量，毒性最小。我们将使用PAC作为疾病原型开发我们新型的多靶抑制剂。在AIM 1中，我们将合成多达100种基于100种化合物的在铅化合物上以优化肿瘤的摄取，并抑制SHMT2和胞质途径 DNP生物合成。在AIM 2中，我们将测试AIM 1的抗肿瘤电位的类似物，以临床相关 PAC细胞系，肿瘤选择性和质膜和线粒体药物转运，药物代谢和抑制SHMT2和包括DNP生物合成的胞质途径。我们将衡量下游影响在MTOR信号，线粒体呼吸，谷胱甘肽池和活性氧中。在AIM 3中，我们将评估AIM 1和2的化合物的药代动力学，耐受性和体内抗肿瘤活性人类PAC细胞系异种移植和PDX模型以及KPC小鼠PAC模型的毒性/有效试验。我们的铅类似物是“一流的”，我们拟议的研究将提供优化的化合物，以最好抑制SHMT2和下游合成途径。我们预计开发IND的SHMT2/DNP靶向化合物根据我们的研究，提交和临床试验。