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，包括急性髓样白血病（AML）和急性淋巴白血病（ALL）其特征在于堆积在骨髓和干扰中的异常白细胞的快速生长随着正常血细胞的产生。尽管在AML的治疗结果中取得了巨大进展，但更多超过一半的年轻患者和约90％的老年患者仍然死于疾病。虽然可以实现在超过80％的患有所有人的受影响儿童中，只有20-40％的成年人得到治愈。因此，迫切需要为AML和所有人开发新的治疗方法。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目标。目前，几种小分子MDM2抑制剂正在接受癌症治疗的临床试验，包括 AML。尽管有潜在的希望，小分子MDM2抑制剂可以显着上调MDM2 表达，这可能会限制其潜在的临床功效，并且由于 MDM2蛋白的致癌活性。因此，需要新的治疗策略以更有效地定位 MDM2用于提高功效，降低副作用并克服抗性。我们已经设计了靶向蛋白水解的嵌合体（Protac）小分子以有效诱导 MDM2蛋白的降解（以下称为MDM2降解器）并研究了其治疗潜力以及体外和体内急性白血病模型中的作用机理。我们的初步数据强烈建议靶向MDM2降解是一种新颖且非常令人兴奋的治疗方法白血病。通过靶向MDM2来开发一种新的治疗急性白血病的疗法退化，我们建议执行以下特定目标：目标1：设计和合成新的MDM2降解器以进一步优化其细胞效力，药代动力学和体内功效。目标2：使用人类和AML细胞系对其体外活性和作用机理的研究，以及来自患者的急性白血病样品。目标3：确定其代谢稳定性，药代动力学，体内抗癌活性人类急性白血病及其在小鼠中的潜在毒性。据我们所知，我们的实验室是第一个开发Protac小分子MDM2的人退化器。该项目成功地执行了，将带来第一类，高度优化的MDM2小型分子降解器降至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。