Novel Aureolic Acid-Type Antitumor Agents

新型金黄色酸型抗肿瘤剂

• 批准号: 8265680
• 负责人: Jurgen T Rohr
• 金额: $ 23.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265680
• 关键词: Address; Adverse effects; Anabolism; Antineoplastic Agents; Arthritis; Biochemical; Biological Factors; Cancer Cell Growth; Chromomycin A3; Chromomycins; DNA; Disease; Engineering; Enzymes; Funding; Generations; Goals; Hypercalcemia; In Vitro; Investigation; Lead; Methods; Oxidoreductase; Oxygenases; Pathway interactions; Pattern; Pharmaceutical Preparations; Plicamycin; Process; Production; Property; Proteins; Proto-Oncogenes; Refractory; Research; Research Project Grants; Role; SRC gene; Signal Transduction Pathway; Specificity; Substrate Specificity; Therapeutic Index; Toxic effect; Work; analog; anticancer activity; antitumor agent; c-myc Genes; chemotherapy; chromomycin; combinatorial; crosslink; design; enzyme mechanism; glycosyltransferase; improved; in vivo; interest; nervous system disorder; novel; olivomycin A; polyketide synthase; protein structure; public health relevance; research study; sugar; tool; tumor

DESCRIPTION (provided by applicant): Aureolic acid-type anticancer agents, such as mithramycin (MTM) or chromomycin (CMM), are potent anticancer drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways towards various proto-oncogenes including c-myc and c-src, the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly, MTM is important, and has become a popular biochemical tool to study Sp-dependent signal transduction pathways, but due to its toxic side effects is rarely used as anticancer agent, except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However, MTM was recently identified as a potential lead drug against neurological diseases, arthritis, and for the treatment of hematologic disorders. All these new applications require only very small, less toxic concentrations of the drug, although the mode-of- action in these contexts remains obscure. MTM's biosynthesis has been studied intensely during the previous funding period of this research project, and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and new MTM-analogues. Two of these analogues, MTM SK and MTM SDK, showed a much better anticancer activity profile with a greatly improved therapeutic index than MTM itself. These new drugs deserve further investigations. During the previous biosynthetic studies biosynthetic intriguing and interesting key enzymes were discovered, which need to be further investigated, particularly oxygenase MtmOIV, Ketoreductase MtmW, glycosyltransferases MtmGIV, MtmGIII, MtmGII, MtmGI, and other, early acting post-polyketide synthase tailoring oxygenases and reductases. The goal is to understand the role and mechanisms of these enzymes in the MTM biosynthesis, and to optimize them for the engineering of novel MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and CMM pathways and to generate new MTM analogues applying combinatorial biosynthesis, (b) to analyze intriguing oxygenases and reductases, (c) to investigate and improve the substrate specificity of glycosyltransferases, (d) to study in vitro and in vivo MTM SK, MTM SDK and other promising MTM analogues developed during the project. PUBLIC HEALTH RELEVANCE: The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful mainly as anticancer drugs, but also as drugs to treat neurological diseases, arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis, in-depth research of the biosynthetic machinery including key enzymes will be explored.

描述（申请人提供）：金黄色酸类抗癌药物，如光神霉素（MTM）或色霉素（CMM），是具有独特作用方式的强效抗癌药物。它们通过交联富含 GC 的 DNA 来抑制癌细胞的生长，从而关闭针对各种原癌基因（包括 c-myc 和 c-src）的特异性蛋白 (Sp) 依赖性途径，后者与这些药物发现的独特的低钙活性有关。特别是，MTM很重要，并已成为研究Sp依赖性信号转导途径的流行生化工具，但由于其毒副作用，除了治疗其他化疗难治性的肿瘤高钙血症外，很少用作抗癌药物。然而，MTM 最近被确定为对抗神经系统疾病、关节炎和血液系统疾病的潜在先导药物。所有这些新应用只需要非常小的、毒性较低的药物浓度，尽管在这些情况下的作用方式仍然不清楚。在该研究项目的前期资助期间，对 MTM 的生物合成进行了深入研究，随后进行的组合生物合成工作揭示了各种生物合成中间体和新的 MTM 类似物。其中两种类似物 MTM SK 和 MTM SDK 表现出比 MTM 本身更好的抗癌活性，并且治疗指数大大提高。这些新药值得进一步研究。在之前的生物合成研究中，发现了一些有趣的生物合成关键酶，需要进一步研究，特别是加氧酶 MtmOIV、酮还原酶 MtmW、糖基转移酶 MtmGIV、MtmGIII、MtmGII、MtmGI 和其他早期作用的后聚酮合酶定制加氧酶和 还原酶。目标是了解这些酶在 MTM 生物合成中的作用和机制，并优化它们以用于新型 MTM 衍生物的工程设计。计划（a）进一步研究MTM和CMM途径尚不清楚的生物合成步骤和机制，并应用组合生物合成产生新的MTM类似物，（b）分析有趣的加氧酶和还原酶，（c）研究和提高糖基转移酶的底物特异性，（d）研究体外和体内MTM SK， MTM SDK 和项目期间开发的其他有前景的 MTM 类似物。 公共健康相关性：拟议的工作旨在开发和精制新一代金黄色酸型天然产物类似物，其毒性显着降低，主要用作抗癌药物，也可用作治疗神经系统疾病、关节炎和血液系统疾病的药物。为了通过组合生物合成生产这些微调药物，将探索对包括关键酶在内的生物合成机制的深入研究。