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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：
10541877
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/10541877
关键词：
Acute Anabolism Antineoplastic Agents Biological Assay Cancer cell line Carbon Cell membrane Cells Characteristics Clinical Trials Collaborations Colon Carcinoma Colorectal Cancer Coupled Cytosol Development Disease Disease remission Dose Drug Delivery Systems Drug Kinetics Drug Transport Enzymes Epithelial Cells Epithelial ovarian cancer Equilibrium Evaluation Exhibits FDA approved FRAP1 gene Genetically Engineered Mouse Glutathione Glycine Glycine Hydroxymethyltransferase Human Hydroxymethyltransferases Hypoxia 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 Proliferating Protons Purines Pyrimidine Reactive Oxygen Species Recovery Regulation Research Respiration Ribonucleotides Role SLC19A1 gene Series Serine Severe Combined Immunodeficiency Signal Transduction Source Structure Survivors Testing Time Toxic effect Transplantation X-Ray Crystallography Xenograft Model Xenograft procedure advanced disease analog antitumor agent cancer care cancer cell clinical care clinically relevant drug discovery drug metabolism 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 tumor microenvironment 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.

摘要