Development of a novel small molecule RPN13 inhibitor and therapeutic for advanced ovarian cancer patients

开发新型小分子 RPN13 抑制剂和治疗晚期卵巢癌患者的药物

基本信息

批准号：
10760824
负责人：
RAVI KUMAR ANCHOORI
金额：
$ 86.84万
依托单位：
UP THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760824
关键词：
Acute Address Antigens Apoptosis Australia Award Biochemical Biological Assay Blood Body Weight Changes Bortezomib CA-125 Antigen Cancer Model Cancer Patient Cancer cell line Canis familiaris Carboplatin Cardiotoxicity Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Trials Country Data Deubiquitination Development Dose Dose Limiting Drug Targeting Drug resistance Effectiveness Epithelial ovarian cancer Exhibits Female Formulation Goals Greater sac of peritoneum Gynecologic Pathology Half-Life Human Improve Access Industry Lead Legal patent Licensing Liquid substance Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mantle Cell Lymphoma Marketing Medical Medical Oncologist Molecular Weight Monitor Multiple Myeloma Mus Neutropenia Normal Cell Normal tissue morphology Nucleosome Core Particle Operative Surgical Procedures Organ Ovarian Paclitaxel Patients Peptides Peripheral Nerves Peripheral Nervous System Diseases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Platinum Platinum Compounds Poly(ADP-ribose) Polymerase Inhibitor Predisposition Process Property Proteasome Inhibition Proteasome Inhibitor Proteins Rattus Recurrence Regimen Resistance Safety Scientist Solid Solid Neoplasm Speed Stress Structure Survival Rate Symptoms TP53 gene Testing Therapeutic Therapeutic Index Thrombocytopenia Tissues Toxic effect Toxicology Treatment Efficacy Tumor Debulking Tumor Tissue Ubiquitin Universities Validation Vascular Endothelial Growth Factors Vertebral column analog anticancer activity behavior test cancer cell cancer therapy cell killing chemotherapy design drug candidate endoplasmic reticulum stress experience improved improved outcome in vitro activity in vivo inhibitor manufacture method development misfolded protein mouse model multicatalytic endopeptidase complex neoplastic cell neurophysiology neurotoxicity novel novel therapeutics patient derived xenograft model peptide drug pharmacokinetics and pharmacodynamics preclinical development protein aggregation protein metabolism proteotoxicity receptor refractory cancer response safety study side effect small molecule small molecule inhibitor standard of care targeted agent therapeutic evaluation treatment response tumor tumor xenograft ubiquitin isopeptidase

项目摘要

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy despite aggressive surgery and toxic chemotherapies. More effective and safer targeted drugs are urgently needed to address this unmet medical need. Compared to normal tissues, EOC exhibits aberrant proteasome function that triggers accumulation of high molecular weight polyubiqutinated and misfolded protein aggregates. Because of this unresolved proteotoxic stress, EOC cell lines are highly susceptible to proteasome inhibitors. While highly effective against liquid cancers like multiple myeloma, unfortunately the licensed 20S proteasome inhibitors, such as bortezomib, have proven ineffective against solid tumors, including EOC. This reflects limited tissue access for these peptide-based drugs and dose-limiting toxicities, notably peripheral neuropathy, thrombocytopenia and neutropenia. Up284 is a proprietary upstream (19S) proteasome inhibitor with a novel target and mechanism, RPN13 inhibition, and a structure designed to overcome the limitations of the licensed drugs with respect to limited potency (Up284 blocks substrate recognition and deubiquitination by the 19S rather than just one of the three 20S catalytic activities), poor activity against solid tumors (Up284 has a novel spiro structure with improved drug-like properties compared to peptide-based 20S inhibitors, and promotes antigen-representation by tumor cells), key toxicities of peripheral neuropathy (Not clinically apparent with Up284 in initial murine studies) and thrombocytopenia and neutropenia (Up284 spares the immunoproteasome and lacks these side effects). Up284 shows broad anticancer activity in vitro, including against EOC lines selected for platinum resistance, with a robust therapeutic index and a promising safety profile, and the ability to control xenograft tumor in an orthotopic mouse model of EOC. This promising data reflects our extensive medicinal chemistry effort to achieve drug-like properties and a patent has been awarded in US (pending in other countries) to cover the novel backbone and lead compounds. Murine data indicate Up284 has favorable pharmacodynamics and confirm the novel mechanism of action in vivo. By inhibiting proteasome ubiquitin receptor RPN13 function and its associated deubiquitinase activity, Up284 produces more rapid accumulation of larger molecular weight polyubiquinated protein aggregates than the 20S inhibitors. These toxic misfolded protein aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR) and thus Up284 more rapidly triggers p53-independent apoptosis than 20S inhibitor. To support an IND application to FDA, we propose: Aim 1: Assessing toxicity & Peripheral Neuropathy (PN) in mice treated IP vs IV with Up284 vs. bortezomib (months 1-3). Aim 2: Mouse clinical trial: Testing therapeutic efficacy of Up284 delivered IP vs IV against 13 ovarian PDX models (months 3-7); Aim 3: Process development, GLP manufacture, formulation stability & GLP bioanalytical method development of Up284 (months 7-24); Aims 4 & 5: GLP toxicology and safety studies of Up284 in rats & dogs (months 15-24).

尽管手术和有毒化学疗法。迫切需要更有效，更安全的靶向药物来解决这种未定的药物医疗需求。与正常组织相比，EOC表现出异常的蛋白酶体功能，触发高分子量聚氨基量和错误折叠蛋白聚集体的积累。因为这未解决的蛋白毒性应激，EOC细胞系高度容易受到蛋白酶体抑制剂的影响。虽然很高对液体癌等液体癌的有效有效，不幸的是，获得许可的20S蛋白酶体抑制剂，如硼替佐米，已证明对包括EOC在内的实体瘤被证明无效。这反映了有限的组织这些基于肽的药物和剂量限制毒性的访问，特别是周围神经病，血小板减少症和中性粒细胞减少症。 UP284是专有上游（19S）蛋白酶体抑制剂，带有小说目标和机制，RPN13抑制作用以及旨在克服许可的局限性的结构关于有限效力的药物（UP284阻止了19s的底物识别和去泛素化而不是仅仅三个20催化活性），而是对实体瘤的活性不佳（UP284具有与基于肽的20S抑制剂相比促进肿瘤细胞的抗原表现），是周围神经病的关键毒性（不是临床上的在最初的鼠研究中具有UP284的明显）和血小板减少症和中性粒细胞减少症（UP284备用免疫蛋白酶体，缺乏这些副作用）。 UP284在体外显示出广泛的抗癌活性，包括针对选择用于铂电阻的EOC线，具有强大的治疗指数和有前途的安全性，以及在EOC的原位小鼠模型中控制异种移植肿瘤的能力。这个有希望的数据反映了我们广泛的药物化学努力以实现类似药物的特性，并在美国获得了专利（在其他国家 /地区待定）涵盖了新颖的骨干和铅化合物。鼠数据表明UP284具有有利的药效学并确认体内作用的新型机制。通过抑制蛋白酶体泛素受体RPN13功能及其相关的去泛素酶活性，UP284产生更快的比20S抑制剂较大的分子量多偶联蛋白聚集体的积累。这些有毒错误折叠的蛋白质聚集体产生未解决的ER应力，激活规范展开的蛋白响应（UPR），因此与20S抑制剂相比，响应（UPR）更快地触发了p53独立的凋亡。支持我们建议：目标1：评估治疗的小鼠中的毒性和周围神经病（PN） IP vs IV具有UP284 vs. Bortezomib（1-3个月）。目标2：鼠标临床试验：测试治疗功效 UP284针对13个卵巢PDX模型（3-7个月）提供了IP与IV；目标3：过程开发，GLP UP284的制造，配方稳定性和GLP生物分析方法开发（7-24个月）；目标4＆ 5：在大鼠和狗中的GLP毒理学和安全研究284（15-24个月）。