PROTACs for pancreatic cancer therapy

PROTAC 用于胰腺癌治疗

• 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
• 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

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）是一种致命的疾病，5年生存率极低， PDAC患者为9%。这一发人深省的统计数据表明需要新的治疗选择。绝 大多数（约90%）PDAC患者携带功能获得性Kras突变，可激活下游信号传导 to drive驱动tumorigenesis肿瘤. Kras激活的信号分子之一是IKKb。细胞因子TNFa是一种 充分表征的分子，也通过丝氨酸残基的磷酸化激活IKKb（S177和S181） 在它的激活回路中。对手术切除的肿瘤样本的分析显示肿瘤中存在TNF α， 约50%的癌症的微环境。一致的是，在肿瘤样本中， 观察到TNF α和p-IKKb的存在。我们分析了从UNMC快速获得的PDAC样品， 尸检胰腺程序，发现原发性肿瘤和肝脏的PDAC细胞中p-IKKb水平升高 与邻近的正常组织相比。从这些观察中得出的一个可检验的假设是， p-IKKb在存在肿瘤相关突变（如KrasG 12 D）的情况下表现出致癌功能。为了验证这一 假设，我们产生的小鼠表达组成型激活IKKb（IKKbS 177 E，S181 E）的存在下， KrasG12D。我们观察到IKKbS 177 E、S181 E的强制表达显著加速了KrasG 12 D驱动的细胞凋亡。 胰腺癌（中位生存期< 2周）。我们的KrasG 12 D; p53（-/-）小鼠队列变得濒死~ 5-6 这与报告的研究结果一致。值得注意的是，胰腺特异性IKKb（-/-） 阻断KrasG 12 D小鼠中PDAC的发展。这些研究表明，p-IKKb表现出强致癌性， 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 旨在绑定/占据其目标并执行其功能。在这种情况下药物的疗效 与药物在靶标上的占据时间相关（占据驱动模型）。的挑战之一 这种方法具有剂量限制毒性，因为仍然很难准确预测所需剂量 需要在患者体内植入靶点。一种新兴的事件驱动方法为 经典的药物发现方法。在这个创新的模型中，药物作为催化剂， 将细胞蛋白质破坏机制转化为目标。这些催化剂被称为PROteolysis 靶向嵌合体（PROTAC）。它们由两个配体通过接头缀合组成。的一个配体 PROTAC与目标靶标结合，另一种配体与E3连接酶结合以促进降解 使用内源性细胞机制的靶蛋白。PROTAC的催化性质使剂量- 限制了传统药物的毒性问题。在这个项目中，我们建议应用事件驱动模型 来开发选择性降解p-IKKb的PROTAC。