Small-molecule MDM2 degraders

急性白血病，包括急性髓细胞白血病（AML）和急性淋巴细胞白血病（ALL），是一种常见的白血病。 以不正常的白色血细胞的快速生长为特征，这些血细胞在骨髓中积聚并干扰 与正常血细胞的生成有关。尽管在AML的治疗结果方面取得了很大进展，但更多 超过一半的年轻成年患者和约90%的老年患者仍然死于他们的疾病。在治愈的同时 在超过80%的ALL患儿中，只有20-40%的成人被治愈。因此，迫切需要 为AML和ALL开发新的治疗方法。 人鼠双微体2（MDM 2）蛋白是一种致癌基因，是一种有吸引力的癌症治疗剂 目标几种小分子MDM 2抑制剂目前正在进行癌症治疗的临床试验，包括 急性髓细胞白血病尽管小分子MDM 2抑制剂具有潜在的前景，但它们可以显著上调MDM 2 表达，这可能限制其潜在的临床功效，并且由于其表达而具有不希望的有害作用。 MDM 2蛋白的致癌活性。因此，需要新的治疗策略来更有效地靶向 MDM 2对提高疗效、减少副作用和克服耐药性的作用。 我们设计了蛋白水解靶向嵌合体（PROTAC）小分子， 降解MDM 2蛋白（下文称为MDM 2降解剂）并研究其治疗潜力 以及在体外和体内急性白血病模型中的作用机制。我们的初步数据显示 靶向MDM 2降解是一种新的和非常令人兴奋的治疗方法， 白血病以MDM 2为靶点开发治疗急性白血病的新疗法 我们建议执行以下具体目标： 目的1：设计和合成新的MDM 2降解剂以进一步优化其细胞效力， 药代动力学和体内功效。 目的2：使用人ALL和AML细胞系研究其体外活性和作用机制， 急性白血病患者的样本。 目的3：测定它们在小鼠模型中的代谢稳定性、药代动力学、体内抗癌活性 人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MDM 2的实验室。 堕落者该项目成功实施后，将带来一流的、高度优化的MDM 2小型- 分子降解剂进入先进的临床前开发和临床试验作为一种新的治疗方法， 急性白血病

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.