Novel anthraquinones induce apoptosis by disruption MDM2/MDM4 interactions

描述(申请人提供)：在癌症治疗中，关键是专注于癌症特异性靶点，从而减少副作用。沿着这一思路，我们有兴趣探索使用某些蒽醌类似物来靶向MDM2和/或MDM4的可能性，以开发癌症治疗方案。这一修订的应用是基于对某些蒽醌类似物的广泛初步结果，这些类似物特别抑制MDM2和MDM4之间的相互作用，从而提高P53的水平，进而导致癌细胞凋亡。对急性淋巴细胞白血病(ALL)小鼠模型的初步动物研究表明，仅治疗两周后，一年内(实验持续时间)治愈，而所有未治疗的小鼠如预期的那样在45天内死亡。初步研究还表明，已鉴定的化合物对正常细胞以及包括心脏、肾脏和肝脏的病理研究在内的动物研究显示出最小或没有毒性，这可能是因为MDM2和MDM4的水平只在癌症中升高，而不是正常细胞。在这项应用中，我们计划了解和验证机制(S)，并研究抑制mdm2-mdm4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拥有丰富的经验。具体目标包括：(1)研究其诱导细胞凋亡的构效关系(SAR)；(2)确定其作用的分子机制(S)；(3)利用动物模型进一步确定开发可作为所有治疗候选药物的可能性。在拟议的工作完成后，我们希望：(1)充分展示靶向MDM2-MDM4相互作用作为开发新抗癌药物的可能性；(2)确定这类蒽醌类化合物的分子机制和构效关系；(3)全面建立用于进一步临床前评估的动物模型；以及(4)可能确定临床前GLP/GMP工作的可行候选者，为未来的临床研究做准备。

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.