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UPR Activators for Cancer Therapy

用于癌症治疗的 UPR 激活剂

基本信息

批准号：
10357411
负责人：
Amarnath Natarajan
金额：
$ 35.06万
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：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10357411
关键词：
Acidosis Address Alkynes Antineoplastic Agents Apoptosis Avidin Azides Biotin Calcium Cancer Model Cancer cell line Cells Chemicals Chemistry Clinical Cysteine Development Endoplasmic Reticulum Evaluation Failure Foundations Goals Growth Hematologic Neoplasms In Situ Isatin Libraries Malignant Neoplasms Malignant neoplasm of ovary Mediating Mitochondria Modality Modification Normal Cell Nuclear Oncogenes Patients Pharmacodynamics Process Proteasome Inhibitor Proteins Proteome Pump Reporting Signal Transduction Solid Neoplasm Stress Structure-Activity Relationship Surface Testing Thapsigargin Therapeutic Toxic effect Translating Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitinated Protein Degradation Up-Regulation Velcade Xenograft Model analog cancer cell cancer therapy crosslink design dimer endoplasmic reticulum stress experience imaging study improved in vivo in vivo Model inhibitor link protein live cell imaging misfolded protein novel novel therapeutics nutrient deprivation oncogene addiction ovarian neoplasm pancreatic cancer model programs proteostasis response small molecule stressor success synergism trafficking tumor growth

项目摘要

Project Summary / Abstract The major goal in this application is to evaluate isatin-derived spirocyclic dimers as novel unfolded protein response (UPR) activators in proof-of-concept studies. Despite the dynamic changes in protein levels, protein homeostasis is maintained by a combination of tightly controlled processes which include synthesis, folding, trafficking and degradation. Accumulation of unfolded / misfolded proteins in the ER due to cell intrinsic and / or extrinsic signals results in the activation of UPR, an adaptation mechanism. Failure to resolve this results in irremediable ER stress and triggers UPR mediated programmed cell death. Cell intrinsic situations in cancer such as loss of tumor suppressor gene or oncogene addication result in higher basal UPR levels. Cancer cells maintain the higher basal UPR levels through upregulation of UPR associated proteins. The higher basal UPR levels in cancer cells provides a therapeutic window that can be exploited by UPR activators. This has been attributed to the success of proteasome inhibitors in the treatment of hematological malignancies. Although the success of proteasome inhibitors validates activation of UPR as a therapeutic modality, the need for UPR activators with novel mechanisms of action (MOA) is exemplified by the failure of proteasome inhibitors in patients with solid tumors. In this application we will address the above need by focusing on the development of a UPR activator with a novel MOA. We have identified an isatin-derived spirocyclic dimer (n7) that activates UPR in both normal and cancer cells but selectively induces apoptosis in cancer cells. Here we propose to continue the development of the novel chemical entity n7 through the following specific aims. Aim 1 will focus on characterization of n7 MOA, aim 2 will focus on structure activity relationship through synthesis and evaluation of n7 analogs and aim 3 will assess the efficacy of n7 or an improved UPR activator in in vivo models. Successful completion of the proposed aims will provide critical proof-of-concept for translating isatin-derived spirocyclic dimers as UPR activators.

项目概要/摘要本申请的主要目标是评估靛红衍生的螺环二聚体作为新型未折叠的概念验证研究中的蛋白质反应（UPR）激活剂。尽管蛋白质水平发生动态变化，蛋白质稳态是通过严格控制的过程组合来维持的，包括合成、折叠、运输和降解。由于细胞内在的原因，未折叠/错误折叠的蛋白质在内质网中积累和/或外在信号导致 UPR（一种适应机制）的激活。无法解决此问题导致不可挽回的内质网应激并触发 UPR 介导的程序性细胞死亡。细胞内在情况癌症，例如肿瘤抑制基因的缺失或癌基因成瘾，会导致基础 UPR 水平升高。癌细胞通过上调 UPR 相关蛋白来维持较高的基础 UPR 水平。这癌细胞中较高的基础 UPR 水平提供了 UPR 激活剂可以利用的治疗窗口。这归因于蛋白酶体抑制剂在治疗血液病方面的成功恶性肿瘤。尽管蛋白酶体抑制剂的成功验证了 UPR 的激活作为一种治疗方法模态，对具有新颖作用机制（MOA）的UPR激活剂的需求以失败为例实体瘤患者的蛋白酶体抑制剂。在此应用程序中，我们将通过以下方式解决上述需求专注于开发具有新型 MOA 的 UPR 活化剂。我们已经鉴定出一种源自靛红的螺环二聚体 (n7) 可激活正常细胞和癌细胞中的 UPR，但选择性诱导细胞凋亡癌细胞。在这里，我们建议通过以下方式继续开发新型化学实体n7：遵循特定目标。目标 1 将重点关注 n7 MOA 的表征，目标 2 将重点关注结构活性通过合成和评估 n7 类似物建立关系，目标 3 将评估 n7 或 n7 类似物的功效改进体内模型中的 UPR 激活剂。成功完成拟议目标将提供关键将靛红衍生的螺环二聚体转化为 UPR 激活剂的概念验证。