Development of small molecule RPN13 inhibitors for Treatment of Glioblastoma

开发治疗胶质母细胞瘤的小分子 RPN13 抑制剂

基本信息

批准号：
10545359
负责人：
RAVI KUMAR ANCHOORI
金额：
$ 40万
依托单位：
UP THERAPEUTICS, INC.
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：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545359
关键词：
Aftercare Alkylating Agents Apoptosis Apoptotic BALB/c Nude Mouse Back Behavioral Binding Biological Assay Biological Markers Blood - brain barrier anatomy Blood Chemical Analysis Bortezomib Brain Brain Neoplasms Cell Death Cell Line Cells Characteristics Chemistry Chemotherapy and/or radiation Cisplatin Complex Core Facility DNA Data Dependence Development Dose Drug Design Drug or chemical Tissue Distribution FDA approved Family Female Financial Hardship Firefly Luciferases Formulation Genetic Glioblastoma Goals Growth Growth Factor Hematologic Neoplasms High Pressure Liquid Chromatography Histopathology Image In Vitro In complete remission Lead Malignant neoplasm of brain Malignant neoplasm of ovary Measures Medical Modeling Mus Normal tissue morphology Nude Mice Operative Surgical Procedures Oral Patients Pattern Pharmaceutical Preparations Pharmacology Phase Phenotype Plasma Production Proteasome Inhibition Proteasome Inhibitor Proteins Radiation therapy Reactive Oxygen Species Regimen Reporter Resistance Route Safety Serum-Free Culture Media Signal Transduction Small Business Technology Transfer Research Solid Neoplasm Solubility Specificity Stress Survival Rate Testing Therapeutic Time Tissues Toxic effect Toxicology Translations Treatment Cost Tumor Tissue Ubiquitin Universities Xenograft procedure aqueous attenuation base burden of illness cancer type cost cost estimate cytotoxic endoplasmic reticulum stress experimental study in vivo in vivo imaging system inhibitor male meetings mortality statistics multicatalytic endopeptidase complex new therapeutic target novel novel anticancer drug novel therapeutics ovarian neoplasm partial response proteotoxicity prototype receptor small molecule small molecule inhibitor standard care success targeted cancer therapy targeted treatment temozolomide transplant model tumor tumor growth virtual

项目摘要

Abstract. Glioblastoma (GBM) is an aggressive and deadly brain cancer with a one year median survival due to the lack of effective targeted treatments. Our goal is to develop a small molecule inhibitor targeting RPN13 protein in the 19S proteasome complex as a new drug for GBM. RPN13 is a proteasome ubiquitin receptor that recognizes ubiquitin-conjugated proteins that are thus tagged for degradation via the 20S proteasome enzymatic complex. GBM is highly sensitive to proteasome inhibition due to its aggressive growth and accumulation of misfolded polyubiquitinated proteins that is insufficiently managed despite increased proteasome levels and enhanced proteasome activity (i.e. proteotoxic stress). Up Therapeutics judiciously designed drug-like RPN13 inhibitors to overcome limitations in the prototype RPN13 inhibitor RA190 identified at Johns Hopkins University. We selected Up284 as lead compound based upon our preliminary studies showing drug-like characteristics, specificity (binding to Cys88 of RPN13), and proteasome inhibition that produces a cytotoxic accumulation of polyUb proteins, ER stress, and reactive oxygen species. Up284 treatment selectively triggers apoptosis in solid tumor types including GBM cell lines and oncospheres. A suitable Up284 formulation was selected by measuring aqueous solubility, stability and on-target activity in mice imaged using a proteasome-dependent in vivo reporter. Up284 can be administered i.v. or orally, and it penetrates through the BBB. As a proof of concept for treatment of GBM, Up284 demonstrated on-target activity in intracranial syngeneic GL261 tumor model by inhibiting proteasome function in tumor tissues. Up284 also regressed tumors in syngeneic, xenograft and spontaneous models of ovarian cancer with acceptable safety profile. Pilot toxicological data indicated Up284 is relatively well tolerated with no evidence of behavioral abnormalities and normal CBC and blood chemistry panel. Given the potential of Up284 as a new cancer drug and GBM as its lead indication, we propose: Goal1a. Determine Up284 dose required in the brain to kill GBM oncospheres (1-3 months): Renewable oncosphere formation in culture is a defining characteristic of certain brain tumor initiating cells. Up284 activity against the growth of GBM oncospheres in the presence and absence of an in vitro BBB layer will be tested. Goal1b. Up284 plasma and tissue distribution studies after IV vs Oral delivery in male & female CD1 mice (3-6 months): Milestones: Identify GBM therapeutic levels needed in the brain and how to deliver Up284 to achieve them. Goal2. Efficacy of Up284 against the growth of orthotopic GBM oncospheres in male & female nude mice (6-12 months). We will test Up284 activity against an intracranial orthotopic transplantation model using firefly luciferase-expressing Br23C oncospheres in nude female mice bearing intracranial Br23C oncospheres or nude male mice bearing JHH-27 oncospheres, a temozolamide resistant model. Milestones: Demonstrate that Up284 provides RECIST-defined complete response (CR) or partial response (PR) against tumor growth using oncosphere-derived GBM models in mouse brain.

抽象的。胶质母细胞瘤 (GBM) 是一种侵袭性且致命的脑癌，中位生存期为一年，原因是缺乏有效的针对性治疗。我们的目标是开发针对 RPN13 的小分子抑制剂 19S蛋白酶体复合物中的蛋白质作为GBM的新药。 RPN13 是一种蛋白酶体泛素受体识别泛素缀合的蛋白质，这些蛋白质因此被标记为通过 20S 蛋白酶体酶促降解复杂的。 GBM 由于其侵袭性生长和蛋白酶体积累而对蛋白酶体抑制高度敏感尽管蛋白酶体水平增加，但错误折叠的多泛素化蛋白仍未得到充分管理，并且增强蛋白酶体活性（即蛋白毒性应激）。 Up Therapeutics 明智地设计了类药 RPN13 克服约翰·霍普金斯大学确定的原型 RPN13 抑制剂 RA190 的局限性。根据我们显示药物样特征的初步研究，我们选择 Up284 作为先导化合物，特异性（与 RPN13 的 Cys88 结合），以及产生细胞毒性积累的蛋白酶体抑制多聚泛素蛋白、内质网应激和活性氧。 Up284 治疗选择性触发固体细胞凋亡肿瘤类型包括 GBM 细胞系和肿瘤球。通过测量选择合适的 Up284 配方使用蛋白酶体依赖性体内报告基因对小鼠进行成像的水溶性、稳定性和靶向活性。 Up284 可以静脉注射给药。或口服，它会穿透血脑屏障。作为治疗概念的证明 GBM 的 Up284 通过抑制蛋白酶体在肿瘤组织中的功能。 Up284 还使同基因、异种移植和自发肿瘤消退具有可接受安全性的卵巢癌模型。试点毒理学数据表明Up284相对较好可以耐受，没有行为异常的证据，并且 CBC 和血液生化检查结果正常。鉴于 Up284作为一种新的抗癌药物的潜力和GBM作为其主要适应症，我们建议：目标1a。确定大脑杀死GBM oncosphere所需的Up284剂量（1-3个月）：可更新培养物中肿瘤球的形成是某些脑肿瘤起始细胞的一个决定性特征。 Up284 活动将测试在体外 BBB 层存在和不存在的情况下对 GBM 甲蚴生长的影响。目标 1b. Up284 雄性和雌性 CD1 小鼠静脉注射与口服给药后的血浆和组织分布研究（3-6 个月）：里程碑：确定大脑所需的 GBM 治疗水平以及如何将 Up284 递送至实现它们。目标2。 Up284 对男性和女性原位 GBM 甲球生长的功效雌性裸鼠（6-12个月）。我们将测试 Up284 针对颅内原位移植的活性在颅内携带 Br23C 的裸雌性小鼠中使用表达萤火虫荧光素酶的 Br23C 甲球模型甲蚴或带有 JHH-27 甲蚴的裸雄性小鼠，一种替莫唑胺耐药模型。里程碑：证明 Up284 提供 RECIST 定义的完全缓解 (CR) 或部分缓解 (PR) 使用小鼠大脑中的肿瘤生长模型进行肿瘤生长。