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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）。其特点是异常白细胞快速生长，在骨髓中积聚并干扰随着正常血细胞的产生。尽管 AML 的治疗效果取得了巨大进步，但超过一半的年轻患者和约 90% 的老年患者仍然死于疾病。在达到治愈的同时在超过 80% 的 ALL 受影响儿童中，只有 20-40% 的成人被治愈。因此，迫切需要开发针对 AML 和 ALL 的新治疗方法。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药物目标。几种小分子 MDM2 抑制剂目前正处于癌症治疗的临床试验中，包括反洗钱。尽管小分子 MDM2 抑制剂具有潜在的前景，但它可以显着上调 MDM2 表达，这可能会限制其潜在的临床功效，并由于 MDM2 蛋白的致癌活性。因此需要新的治疗策略来更有效地靶向 MDM2 致力于提高疗效、减少副作用和克服耐药性。我们设计了蛋白水解靶向嵌合体（PROTAC）小分子来有效诱导降解 MDM2 蛋白（以下称为 MDM2 降解剂）并研究其治疗潜力以及体外和体内急性白血病模型的作用机制。我们的初步数据强烈表明靶向 MDM2 降解是一种新颖且非常令人兴奋的治疗方法，用于治疗急性白血病。致力于开发一种针对 MDM2 的治疗急性白血病的新疗法退化，我们建议执行以下具体目标：目标 1：设计和合成新的 MDM2 降解剂以进一步优化其细胞效力，药代动力学和体内功效。目标 2：使用人类 ALL 和 AML 细胞系研究其体外活性和作用机制，来自患者的急性白血病样本。目标 3：测定其在小鼠模型中的代谢稳定性、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，我们实验室是第一个开发PROTAC小分子MDM2的实验室降解者。如果成功执行，该项目将带来一流的、高度优化的 MDM2 小型分子降解剂进入先进的临床前开发和临床试验作为治疗的新疗法急性白血病。