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).

尽管需要积极的手术和治疗，上皮性卵巢癌（EOC）仍然是最致命的妇科恶性肿瘤。有毒的化疗。迫切需要更有效、更安全的靶向药物来解决这一未满足的问题医疗需要。与正常组织相比，EOC 表现出异常的蛋白酶体功能，从而触发高分子量多聚泛素化和错误折叠的蛋白质聚集体的积累。因为这由于未解决的蛋白毒性应激，EOC 细胞系对蛋白酶体抑制剂高度敏感。虽然高度有效对抗多发性骨髓瘤等液体癌症，不幸的是获得许可的 20S 蛋白酶体抑制剂，硼替佐米等药物已被证明对包括 EOC 在内的实体瘤无效。这反映了有限的组织获得这些基于肽的药物和剂量限制性毒性，特别是周围神经病变，血小板减少症和中性粒细胞减少症。 Up284 是一种专有的上游 (19S) 蛋白酶体抑制剂，具有新颖的靶点和机制、RPN13 抑制以及旨在克服许可限制的结构药物效力有限（Up284 阻断 19S 的底物识别和去泛素化而不仅仅是三种 20S 催化活性之一），对实体瘤的活性较差（Up284 具有与基于肽的 20S 抑制剂相比，新型螺环结构具有改善的药物样特性，以及促进肿瘤细胞的抗原表达），周围神经病变的关键毒性（临床上没有在最初的小鼠研究中，Up284 明显）以及血小板减少症和中性粒细胞减少症（Up284 避免了免疫蛋白酶体并且缺乏这些副作用）。 Up284 在体外显示出广泛的抗癌活性，包括针对针对铂类耐药而选择的 EOC 系，具有稳健的治疗指数和有前景的安全性，以及在 EOC 原位小鼠模型中控制异种移植肿瘤的能力。这一充满希望的数据反映了我们为实现药物特性而进行的广泛药物化学努力，并已在美国获得专利（其他国家正在等待）涵盖新型主链和先导化合物。小鼠数据表明 Up284 良好的药效学并证实了体内的新作用机制。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 产生更快速与 20S 抑制剂相比，更大分子量的多泛素化蛋白聚集体的积累。这些有毒的错误折叠的蛋白质聚集体产生未解决的内质网应激，激活经典的未折叠蛋白质响应 (UPR) 以及 Up284 比 20S 抑制剂更快速地触发 p53 独立的细胞凋亡。支持在向 FDA 提交 IND 申请时，我们建议：目标 1：评估接受治疗的小鼠的毒性和周围神经病变 (PN) IP 与 Up284 IV 对比硼替佐米（第 1-3 个月）。目标 2：小鼠临床试验：测试治疗效果 Up284 针对 13 个卵巢 PDX 模型（第 3-7 个月）进行了 IP 与 IV 比较；目标 3：工艺开发、GLP Up284 的制造、配方稳定性和 GLP 生物分析方法开发（第 7-24 个月）；目标 4 & 图 5：Up284 在大鼠和狗中的 GLP 毒理学和安全性研究（15-24 个月）。