Design of the First Mdm2 Targeting PROTACs for treatment of p53 Mutant or Deficient Cancers

第一个 Mdm2 靶向 PROTAC 的设计用于治疗 p53 突变或缺陷癌症

基本信息

批准号：
10700091
负责人：
CHRISTINE M. EISCHEN
金额：
$ 52.91万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700091
关键词：
26S proteasome Address Affinity Apoptosis Apoptotic Binding Cell Aging Cell Cycle Arrest Cells Cellular Stress Chemical Structure DNA DNA Damage Data Development Drug Kinetics Drug Targeting Evaluation Family member Feedback Genetic Transcription Goals Growth Human Hydrophobicity In Vitro Lead Ligands Lymphoma MDM2 gene Malignant Neoplasms Mediating Metabolic Mus Mutate Mutation N-terminal Neutropenia Oncogenes Patients Pharmaceutical Preparations Pharmacotherapy Phase III Clinical Trials Prevention Property Protac Proteins Proteomics Repair Complex Reporting Resistance Role Safety Series Signal Transduction Site Stress TP53 gene Testing Therapeutic Thrombocytopenia Toxic effect Transactivation Tumor Burden Validation Xenograft Model Xenograft procedure biophysical analysis cancer cell cancer survival clinical efficacy design drug discovery efficacy evaluation efficacy study improved in vivo in vivo Model inhibitor lead optimization loss of function mimicry mutant novel pre-clinical protein degradation research clinical testing sarcoma screening transcription factor tumor tumor initiation tumor progression tumorigenic ubiquitin-protein ligase

项目摘要

Project Summary / Abstract Our proposal focuses on the development of novel Mdm2-targeted proteolysis targeting chimeras (PROTACs) that efficiently degrade Mdm2 in p53 mutant and deficient cancer cells and are expected to target p53- independent functions of Mdm2. Our lead compounds bind with high affinity, degrade Mdm2, kill cancer cells that lack functional p53, and are efficacious in vivo. We have also demonstrated safety and tolerability in vivo, synthetic tractability, metabolic stability, and suitable in vivo exposure in mouse pharmacokinetic studies for in vivo efficacy evaluation. The tumor suppressor p53, a transcription factor, has an essential role in the prevention of human cancer. In the absence of cellular stress, the p53 protein is maintained at low levels due to its binding to Mdm2, an E3 ubiquitin ligase. However, half of all human cancers have inactivated p53 by mutation or deletion. To test if Mdm2 is required for the survival of cancer cells that lack p53 we inducibly deleted Mdm2 in primary murine p53-null lymphoma and sarcoma cells. Mdm2 loss resulted in apoptosis in vitro and in vivo in p53-null cancers, with significantly reduced tumor burden and increased survival benefit. We and others have reported that Mdm2 has p53-independent functions by binding and regulating other proteins, such as the p53 family member, p73, and Nbs1 in the Mre11-Rad50-Nbs1 DNA break repair complex. p73 has a homologous N-terminal transactivation domain to p53 which binds in the same site on Mdm2. Additionally, unlike p53, p73 is rarely inactivated in human cancers. Since Mdm2-p53 inhibitors are not responsive to tumors with inactivated p53, we pursued a PROTAC approach and provide preliminary data to confirm their ability to kill p53 mutated or deficient cancer cells. Our hypothesis is that the degradation of Mdm2 via Mdm2-targeted PROTACs will kill cancers with mutant or deleted p53 by activating the p53-independent activities of Mdm2. We will test this hypothesis with two Specific Aims. Aim 1 will focus on expanding the characterization of our lead Mdm2 targeting compounds and evaluate these in in vivo xenograft models. Aim 2 will be lead optimization of two Mdm2 PROTACs that killed p53 mutant and deleted cancers. The goal of these aims is to have a characterized, effective, and potent Mdm2 PROTAC for clinical evaluation for the treatment of p53-inactivated cancers.

项目摘要 /摘要我们的建议着重于针对嵌合体的新型MDM2靶向蛋白水解的发展在p53突变体和缺乏癌细胞中有效降解MDM2，预计将靶向p53-- MDM2的独立功能。我们的铅化合物与高亲和力结合，降解MDM2，杀死癌细胞缺乏功能性p53，并且在体内具有有效性。我们还证明了体内的安全性和耐受性，在小鼠药代动力学研究中，合成的障碍性，代谢稳定性和适当的体内暴露于体内体内功效评估。抑制肿瘤p53是转录因子，在预防中具有重要作用人类癌症。在没有细胞应激的情况下，p53蛋白由于其结合而保持低水平到MDM2，一种E3泛素连接酶。但是，所有人类癌症中有一半因突变或缺失使p53失活。为了测试缺乏p53的癌细胞存活是否需要MDM2，我们在原代中诱导了MDM2 鼠P53无效淋巴瘤和肉瘤细胞。 MDM2损失导致体外凋亡和体内p53-null 癌症，肿瘤负担大大减轻并增加了生存益处。我们和其他人报告了该MDM2通过结合和调节其他蛋白质（例如p53家族）具有p53独立的功能 MRE11-RAD50-NBS1 DNA断裂修复复合物中的成员，P73和NBS1。 p73具有同源的N末端反式激活结构域与在MDM2上在同一位点结合的p53。另外，与p53不同，p73很少在人类癌症中灭活。由于MDM2-P53抑制剂对p53灭活的肿瘤没有反应，因此我们采用Protac方法并提供初步数据，以确认其杀死P53突变或不足的能力癌细胞。我们的假设是，MDM2通过MDM2靶向的protac降解将杀死癌症通过激活MDM2的p53非依赖性活性，突变体或已删除的p53。我们将用两个具体目标。 AIM 1将专注于扩展我们的铅MDM2靶向化合物的表征和在体内异种移植模型中评估这些模型。 AIM 2将是两个杀死的MDM2 Protac的铅优化 p53突变体和删除的癌症。这些目的的目的是具有特征性，有效和有效的MDM2 Protac用于治疗p53灭活癌症的临床评估。