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（由申请人提供）：金黄色苯甲酸（MTM）或铬霉素（CMM）等黄酸型抗癌剂是具有独特作用方式的有效抗癌药物。它们通过交联富含GC的DNA抑制癌细胞的生长，从而关闭通往各种原始癌基因（包括C-MYC和C-SRC）的特异性蛋白质（SP）依赖性途径，后者与这些药物的独特低钙化活性有关。特别是，MTM很重要，并且已成为研究SP依赖性信号转导途径的流行生化工具，但是由于其毒性副作用很少用作抗癌剂，除了治疗肿瘤高钙性难治性与其他化学疗法的治疗。但是，最近将MTM鉴定为针对神经系统疾病，关节炎和血液学疾病治疗的潜在铅药物。尽管在这些情况下的作用方式仍然晦涩难懂，但所有这些新应用只需要非常小，毒性较小的药物浓度。在该研究项目的上一个资金期间，对MTM的生物合成进行了深入的研究，因此从事组合生物合成工作揭示了各种生物合成中间体和新的MTM Analogues。其中两个类似物MTM SK和MTM SDK表现出比MTM本身更好的抗癌活性特征，其治疗指数大大改善。这些新药值得进一步研究。在先前的生物合成研究期间，发现了生物合成有趣和有趣的关键酶，需要进一步研究，尤其是氧合酶mtmoiv，氯糖基转移酶mtmgiv，mtmgii，mtmgiii，mtmgii，mtmgii，mtmgii，mtmgii，mtmggi and Mtmggi和其他早期，及早的合成均匀的合成，还原酶。目的是了解这些酶在MTM生物合成中的作用和机制，并为新型MTM衍生物的工程进行优化。 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和其他有前途的MTM类似物在该项目期间开发了。 公共卫生相关性：拟议的工作旨在开发和完善新一代的硫酸型天然产物类似物，其毒性明显降低，这将主要用作抗癌药物，也可以作为治疗神经系统疾病，关节炎和血液学疾病的药物。为了通过联合生物合成来实现这些微调药物的生产，将探讨对包括关键酶的生物合成机械的深入研究。