PROTACs for pancreatic cancer therapy

PROTAC 用于胰腺癌治疗

基本信息

批准号：
10027631
负责人：
Amarnath Natarajan
金额：
$ 39.34万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10027631
关键词：
Acute Adenocarcinoma Cell Affect Age-Months Autopsy Binding Binding Sites Biological Assay CDK2 gene CDK4 gene CDK5 gene Cell physiology Cessation of life Chronic Clinic Clinical Trials Complex Computer software Crystallization Development Disease Docking Dose Dose-Limiting Drug Design Drug Industry Drug Modelings Drug Targeting Embryo Event Exhibits Funding Furans Genes Genetic Goals Homologous Gene Human Immunohistochemistry Infection Kinetics Ligand Binding Ligands Liver Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mantle Cell Lymphoma Mediating Modeling Mus Mutate Mutation Nature Neoplasm Metastasis Normal tissue morphology Oncogenic Operative Surgical Procedures Oral cavity Pancreas Pancreatic Ductal Adenocarcinoma Pathologic Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Post-Translational Protein Processing Predisposition Primary Neoplasm Protac Proteins Quinoxalines Reaction Time Regimen Reporting Resected Sampling Serine Signal Transduction Signaling Molecule Solvents Structure Survival Rate TP53 gene Testing Therapeutic Time Toxic effect Ubiquitin analog antitumor effect base cancer therapy catalyst chronic inflammatory disease cohort combat crosslink cytokine design drug development drug discovery drug efficacy gain of function inhibitor/antagonist innovation interest kinase inhibitor liver injury novel novel therapeutics overexpression pancreas development pancreatic cancer model programs screening small molecule therapeutic target tumor tumor growth tumor microenvironment tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with an abysmal 5-year survival rate of < 9% for patients with PDAC. This sobering statistic indicates a need for novel therapeutic options. The vast majority (~90%) of PDAC patients carry a gain-of-function Kras mutation, which activates downstream signaling to drive tumorigenesis. One of these signaling molecules activated by Kras is IKKb. The cytokine, TNFa, is a well characterized molecule that also activates IKKb through phosphorylation of serine residues (S177 and S181) in its activation loop. Analyses of surgically resected tumor samples revealed the presence of TNFa in the tumor microenvironment of ~50% of all cancers. Consistently, in the tumor samples, a perfect correlation between the presence of TNFa and p-IKKb was observed. We analyzed PDAC samples obtained from the UNMC rapid autopsy pancreatic program and found elevated levels of p-IKKb in the PDAC cells of the primary tumor and liver mets when compared to adjacent normal tissue. A testable hypothesis derived from these observations was that p-IKKb exhibits oncogenic function in the presence of tumor associated mutations such as KrasG12D. To test this hypothesis, we generated mice that expressed constitutively activated IKKb (IKKbS177E,S181E) in the presence of KrasG12D. We observed that forced expression of IKKbS177E,S181E dramatically accelerated KrasG12D driven pancreatic cancer (median survival of < 2-weeks). Our cohort of KrasG12D; p53(-/-) mice became moribund ~ 5-6 months of age, which is consistent with reported studies. It is important to note that pancreas-specific IKKb(-/-) blocks the development of PDAC in KrasG12D mice. These studies suggest that p-IKKb exhibits potent oncogenic function and selective targeting of p-IKKb is a viable therapeutic option for PDAC. Traditionally, drugs are designed to bind / occupy their target and inactivate its function. The efficacy of the drug in this scenario correlates with the occupancy time of the drug on target (occupancy driven model). One of the challenges with this approach is dose-limiting toxicity, as it continues to be difficult to accurately predict the necessary dose required to inactivate the target in patients. An emerging event driven approach provides an alternate to the classical drug discovery approach. In this innovative model the drug functions as a catalyst that brings together the cellular protein destruction machinery to the target of interest. These catalysts are called PROteolysis Targeting Chimeras (PROTACs). They are composed of two ligands conjugated through a linker. One ligand of the PROTAC binds to the target of interest and the other ligand binds to an E3 ligase to facilitate the degradation of the target protein using the endogenous cellular machinery. The catalytic nature of PROTACs alleviates dose- limiting toxicity issues observed with traditional drugs. In this project we propose to apply the event driven model to develop PROTACs that will selectively degrade p-IKKb.

项目摘要胰腺导管腺癌（PDAC）是一种致命疾病，其5年生存率<< PDAC患者的9％。这种清醒的统计数据表明需要新的治疗选择。广大大多数（〜90％）的PDAC患者携带功能获得的KRAS突变，该突变激活下游信号传导驱动肿瘤发生。这些信号分子之一是由KRAS激活的IKKB。细胞因子TNFA是一个良好的特征分子也通过丝氨酸残基的磷酸化激活IKKB（S177和S181）在其激活循环中。对手术切除的肿瘤样品的分析显示，肿瘤中存在TNFA 所有癌症的微环境约为50％。一贯，在肿瘤样品中，观察到TNFA和P-IKKB的存在。我们分析了从UNMC快速获得的PDAC样品尸检胰腺计划，发现原发性肿瘤和肝脏PDAC细胞中P-IKKB的水平升高与邻近的正常组织相比，大都能蛋白。从这些观察结果得出的可检验的假设是 P-IKKB在存在相关突变（例如Krasg12d）的情况下表现出致癌功能。测试这个假设，我们生成了在存在下表达组成性激活的IKKB（IKKBS177E，S181E）的小鼠。 Krasg12d。我们观察到IKKBS177E强迫表达S181E急剧加速了Krasg12d驱动胰腺癌（<2周的中位生存期）。我们的Krasg12d队列； p53（ - / - ）小鼠变成垂坠5-6 月大，这与报告的研究一致。重要的是要注意，胰腺特异性IKKB（ - / - ）阻止KRASG12D小鼠PDAC的发展。这些研究表明，P-IKKB表现出有效的致癌性 P-IKKB的功能和选择性靶向是PDAC的可行治疗选择。传统上，毒品是旨在结合 /占据其目标并灭活其功能。在这种情况下，药物的功效与靶标（占用驱动模型）的药物的占用时间相关。挑战之一这种方法是限制剂量的毒性，因为它仍然难以准确预测必要的剂量需要使患者的目标失活。新兴事件驱动的方法为古典药物发现方法。在这种创新的模型中，药物充当催化剂，将细胞蛋白破坏机制达到了感兴趣的目标。这些催化剂称为蛋白水解靶向嵌合体（Protac）。它们由两个通过接头结合的配体组成。一个配体 Protac与感兴趣的靶标结合，其他配体与E3连接酶结合以促进降解使用内源性细胞机械的靶蛋白。 protac的催化性减轻剂量 - 限制传统药物观察到的毒性问题。在这个项目中，我们建议应用事件驱动的模型开发可有选择地降解p-ikkb的protac。