Novel anthraquinones induce apoptosis by disruption MDM2/MDM4 interactions

新型蒽醌通过破坏 MDM2/MDM4 相互作用诱导细胞凋亡

• 批准号: 8783378
• 负责人: Binghe Wang
• 金额: $ 46.03万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783378
• 关键词: Acute Lymphocytic Leukemia; Adverse effects; Animal Model; Animals; Anthraquinones; Antineoplastic Agents; Apoptosis; Area; Biological; Camptothecin; Cell Culture Techniques; Cells; Chemicals; Child; Cisplatin; Clinical Research; Consensus Development; Control Groups; Cytotoxic agent; Development; Dimerization; Disease remission; Doxorubicin; Emodin; Feasibility Studies; Fluorouracil; Future; Gleevec; Goals; Health; Heart; Human; Kidney; Link; Liver; MDM2 gene; Malignant Neoplasms; Mechlorethamine; Methotrexate; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Normal Cell; Paclitaxel; Parents; Patients; Pharmaceutical Preparations; Preparation; Proteins; Refractory; Reporting; Staging; Structure-Activity Relationship; Therapeutic; Therapeutic Agents; Toxic effect; Work; analog; base; cancer cell; cancer therapy; cytotoxicity; drug development; experience; high risk; inhibitor/antagonist; interest; kinase inhibitor; leukemia; mouse model; novel; novel therapeutics; outcome forecast; overexpression; pre-clinical; preclinical evaluation; professor; public health relevance; research study; rhein; success; therapeutic target

DESCRIPTION (provided by applicant): In cancer treatment, the key is to focus on cancer-specific targets and thereby reduce side effects. Along this line, we are interested in exploring the possibility of using certain anthraquinone analogs to target MDM2 and/or MDM4 for the development of cancer treatment options. This revised application is based on extensive preliminary results examining certain anthraquinone analogs, which specifically inhibit the interactions between MDM2 and MDM4 and thus increase the level of p53, which in turn results in apoptosis of cancer cells. Initial animal studies with an acute lymphoblastic leukemia (ALL) mouse model indicated cure at the 1-year point (the duration of the experiments) after only two weeks of treatment, while all mice without treatment died within 45 days as expected. Preliminary studies also suggest that the identified compounds show minimal or no toxicity to normal cells, and in animal studies including pathological studies of heart, kidney, and liver, presumably due to the fact that levels of MDM2 and MDM4 are only elevated in cancer, not normal cells. In this application, we plan to understand and validate the mechanism(s) and examine the feasibility of inhibiting MDM2-MDM4 interaction as a way to develop cancer therapeutics. We plan to use acute lymphoblastic leukemia (ALL) as a model because of our extensive experience in this area. Specific Aims include (1) study the structure-activity relationship (SAR) of the anthraquinone analogs with regard to their ability to induce apoptosis; (2) define the molecular mechanism(s) of action of anthraquinone analogs; and (3) further ascertain the potential of developing anthraquinone analogs as viable candidates for ALL treatment using animal models. Upon completion of the proposed work, we hope to have (1) fully demonstrated the feasibility of targeting MDM2-MDM4 interactions as a way to develop new anticancer agents; (2) defined the molecular mechanism and structure-activity relationship for this class of anthraquinones, (3) fully established animal models for further preclinical evaluation, and (4) possibly identified viable candidates for preclinical GLP/GMP work in preparation for future clinical studies.

描述（由申请人提供）：在癌症治疗中，关键是关注癌症特异性靶点，从而减少副作用。沿着这条线，我们感兴趣的是探索使用某些蒽醌类似物靶向MDM 2和/或MDM 4以开发癌症治疗选择的可能性。这项修订申请是基于对某些蒽醌类似物的广泛初步研究结果，这些蒽醌类似物特异性抑制MDM 2和MDM 4之间的相互作用，从而增加p53的水平，这反过来又导致癌细胞凋亡。用急性淋巴细胞白血病（ALL）小鼠模型进行的初步动物研究表明，在治疗仅两周后的1年时间点（实验持续时间）治愈，而所有未经治疗的小鼠如预期在45天内死亡。初步研究还表明，所鉴定的化合物对正常细胞显示出最小的毒性或没有毒性，并且在包括心脏、肾脏和肝脏的病理学研究的动物研究中，可能是由于MDM 2和MDM 4的水平仅在癌症中升高，而不是在正常细胞中升高。在本申请中，我们计划了解和验证机制，并研究抑制MDM 2-MDM 4相互作用作为开发癌症治疗方法的可行性。我们计划使用急性淋巴细胞白血病（ALL）作为模型，因为我们在这一领域的丰富经验。具体目的包括（1）研究蒽醌类似物诱导细胞凋亡能力的构效关系（SAR）;（2）确定蒽醌类似物作用的分子机制;（3）使用动物模型进一步确定开发蒽醌类似物作为ALL治疗可行候选物的潜力。 完成拟议工作后，我们希望（1）充分证明靶向MDM 2-MDM 4相互作用作为开发新抗癌药物的可行性;（2）明确了这类蒽醌类化合物的作用机制和构效关系;（3）建立了完整的动物模型，为进一步的临床前评价奠定了基础;和（4）为准备未来的临床研究，可能确定了临床前GLP/GMP工作的可行候选者。