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Small-molecule MDM2 degraders

小分子 MDM2 降解剂

基本信息

批准号：
10219177
负责人：
SHAOMENG WANG
金额：
$ 64.7万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219177
关键词：
Accounting Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Affect Age Apoptosis Award Blood Cells Bone Marrow Cell Death Cell Line Cessation of life Child Childhood Clinical Treatment Clinical Trials Data Disease Dose Double Minutes Drug Kinetics Genetic Transcription Goals Human In Vitro Incidence Investigation Laboratories Lead Leukocytes Malignant Neoplasms Messenger RNA Metabolic Mus Oncogenes Oncogenic Patients Phase III Clinical Trials Population Production Protac Proteins Rare Diseases Reporting Research Resistance Sampling Schedule TP53 gene Therapeutic Therapeutic Index Time Toxic effect Treatment outcome Tumor Tissue United States Up-Regulation Xenograft Model acute myeloid leukemia cell anticancer activity cancer clinical trial cancer therapy cell growth clinical development clinical efficacy design human model improved in vitro Model in vitro activity in vivo inhibitor/antagonist mouse model nanomolar novel novel therapeutic intervention novel therapeutics older patient preclinical development protein activation protein protein interaction rapid growth side effect small molecule small molecule inhibitor therapeutic target tumor tumor xenograft young adult

项目摘要

Acute leukemia, including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Despite the great progress made in the treatment outcome of AML, more than half of young adult patients and about 90% of older patients still die from their disease. While cure is achieved in more than 80% of affected children with ALL, only 20-40% of adults are cured. Therefore, there is an urgent need to develop new therapeutic approaches for both AML and ALL. The human murine double minute 2 (MDM2) protein is an oncogene and is an attractive cancer therapeutic target. Several small-molecule MDM2 inhibitors are currently in clinical trials for cancer treatment, including AML. Despite their potential promise, small-molecule MDM2 inhibitors can dramatically upregulate MDM2 expression, which may limit their potential clinical efficacy and have unwanted deleterious effects due to the oncogenic activity of MDM2 protein. New therapeutic strategies are therefore needed to more effectively target MDM2 toward improving efficacy, reducing side effects and overcoming resistance. We have designed proteolysis-targeting chimera (PROTAC) small-molecules to efficiently induce degradation of MDM2 protein (hereafter called MDM2 degraders) and investigated their therapeutic potential and mechanism of action in acute leukemia models in vitro and in vivo. Our preliminary data strongly suggest that targeting MDM2 degradation is a novel and very exciting therapeutic approach for the treatment of acute leukemia. Toward developing a novel therapy for the treatment of acute leukemia by targeting MDM2 degradation, we propose to perform the following specific Aims: Aim 1: Design and synthesis of new MDM2 degraders to further optimize their cellular potencies, pharmacokinetics and in vivo efficacy. Aim 2: Investigation of their in vitro activity and mechanism of action using human ALL and AML cell lines and acute leukemia samples from patients. Aim 3: Determination of their metabolic stability, pharmacokinetics, in vivo anticancer activity in mouse models of human acute leukemia and their potential toxicity in mice. To the best of our knowledge, our laboratory is the first to develop PROTAC small-molecule MDM2 degraders. Successfully performed, this project will bring the first-in-class, highly optimized MDM2 small- molecule degrader into advanced preclinical development and clinical trials as a new therapy for the treatment of acute leukemia.

急性白血病，包括急性髓系白血病(AML)和急性淋巴细胞白血病(ALL)，以异常白血球快速增长为特征的，这些白血球聚集在骨髓中并干扰产生正常的血细胞。尽管急性髓细胞白血病的治疗结果取得了很大进展，但更多的超过一半的年轻成人患者和大约90%的老年患者仍然死于他们的疾病。在实现治愈的同时在80%以上受影响的ALL儿童中，只有20%-40%的成年人痊愈。因此，迫切需要为AML和ALL开发新的治疗方法。人鼠双分钟2(MDM2)蛋白是一种癌基因，是一种有吸引力的癌症治疗方法目标。几种小分子MDM2抑制剂目前正在进行癌症治疗的临床试验，包括 AML。尽管有潜在的希望，小分子MDM2抑制剂可以显著上调MDM2 表达，这可能限制其潜在的临床疗效，并具有有害的影响，因为 MDM2蛋白的致癌活性。因此，需要新的治疗策略来更有效地针对 MDM2用于提高疗效、减少副作用和克服耐药性。我们设计了蛋白质降解靶向嵌合体(PROTAC)小分子来有效地诱导 MDM2蛋白(以下简称MDM2降解物)的降解及其治疗潜力的研究以及在体外和体内急性白血病模型中的作用机制。我们的初步数据强烈表明靶向MDM2降解是治疗急性白血病的一种新的和非常令人兴奋的治疗方法。白血病。靶向MDM2治疗急性白血病的研究进展为解决这一问题，我们建议实现以下具体目标：目标1：设计和合成新的MDM2降解剂，以进一步优化其细胞能力，药代动力学和体内疗效。目的2：用人急性淋巴细胞白血病(ALL)和急性髓系白血病(AML)细胞株研究其体外活性及作用机制。患者的急性白血病样本。目的3：在小鼠模型中测定它们的代谢稳定性、药代动力学和体内抗癌活性人类急性白血病及其对小鼠的潜在毒性。据我们所知，我们的实验室是第一个开发PROTAC小分子MDM2的实验室降落者。成功实施，该项目将带来一流的、高度优化的MDM2小型机- 分子降解剂作为一种新的治疗方法进入高级临床前开发和临床试验死于急性白血病。