Developing a RPN13 inhibitor for the treatment of Quadruple Negative Breast Cancer

开发用于治疗四阴性乳腺癌的 RPN13 抑制剂

• 批准号: 10541089
• 负责人: RAVI KUMAR ANCHOORI
• 金额: $ 5.5万
• 依托单位: UP THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541089
• 关键词: Address; African American; African American population; Androgen Receptor; Apoptosis; Bortezomib; Breast Cancer Patient; Breast Cancer cell line; Cells; Collaborations; Data; Deubiquitination; Development; Dose-Limiting; Drug resistance; ERBB2 gene; Epidermal Growth Factor Receptor; Estrogen Receptors; Health Disparities Research; Hematopoietic; Human; Lead; Legal patent; Medical; Molecular Weight; Multiple Myeloma; Neutropenia; Outcome; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Progesterone Receptors; Prognosis; Property; Proteasome Inhibitor; Proteins; Race; Resistance; Safety; Signal Transduction; Solid Neoplasm; Stress; Structure; Therapeutic; Therapeutic Index; Thrombocytopenia; Toxic effect; Ubiquitin; Vertebral column; Xenograft procedure; anticancer activity; base; cancer subtypes; design; improved; in vitro activity; inhibitor; malignant breast neoplasm; misfolded protein; multicatalytic endopeptidase complex; novel; novel therapeutics; protein aggregation; receptor; response; standard of care; triple-negative invasive breast carcinoma; tumor; tumor xenograft; uptake; Address; African American; African American population; Androgen Receptor; Apoptosis; Bortezomib; Breast Cancer Patient; Breast Cancer cell line; Cells; Collaborations; Data; Deubiquitination; Development; Dose-Limiting; Drug resistance; ERBB2 gene; Epidermal Growth Factor Receptor; Estrogen Receptors; Health Disparities Research; Hematopoietic; Human; Lead; Legal patent; Medical; Molecular Weight; Multiple Myeloma; Neutropenia; Outcome; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Progesterone Receptors; Prognosis; Property; Proteasome Inhibitor; Proteins; Race; Resistance; Safety; Signal Transduction; Solid Neoplasm; Stress; Structure; Therapeutic; Therapeutic Index; Thrombocytopenia; Toxic effect; Ubiquitin; Vertebral column; Xenograft procedure; anticancer activity; base; cancer subtypes; design; improved; in vitro activity; inhibitor; malignant breast neoplasm; misfolded protein; multicatalytic endopeptidase complex; novel; novel therapeutics; protein aggregation; receptor; response; standard of care; triple-negative invasive breast carcinoma; tumor; tumor xenograft; uptake

Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor 2) and AR (androgen receptor), is the breast cancer subtype with the worst prognosis, and QNBC disproportionately afflicts African Americans. It has no standard-of-care treatment targets and thus efficacious and safe treatments must be urgently sought for this unmet medical need, and to address the disparity in breast cancer outcomes. The current proposal is motivated by data showing elevated expression of proteasome subunit RPN13 is associated with both African American race and lower survival in QNBC patients, that RPN13 targeted by our Up284 inhibitor, a strong ongoing collaboration with Dr. Karanam (TU), and the guidance of Dr. Yates (TU) in health disparity research and Dr. Davis (Weill Cornell) in breast cancer subtypes. Both triple negative breast cancer and QNBC cell lines show evidence of greater vulnerability to proteasome inhibitors. However, licensed 20S proteasome inhibitors, e.g. bortezomib, have proven ineffective against solid tumors, with emergence of resistance, and dose limiting toxicities including thrombocytopenia and neutropenia. Up284 has a target and structure designed to overcome the limitations of the licensed drugs with respect to drug resistance (Up284 blocks substrate recognition and deubiquitination rather than just one of the three 20S catalytic activities), poor activity against solid tumors (Up284 has a novel spiro structure with evidence of improved drug access to tumor as compared to peptide-based 20S inhibitors), key toxicities of thrombocytopenia and neutropenia (unlike 20S inhibitors, Up284 does not target the immunoproteasome expressed by hematopoietic cells and does not show these toxicities). Up284 shows broad anticancer activity in vitro, including against QNBC lines with a robust therapeutic index, a promising safety profile and pharmacodynamics, and the ability to control xenograft tumor. This promising data reflects our extensive medicinal chemistry effort to achieve drug-like properties and a patent has been filed globally to cover the novel backbone and lead compounds. By inhibiting proteasome ubiquitin receptor RPN13 function and its associated deubiquitinase activity, Up284 triggers more rapid accumulation and increased molecular weight polyubiquinated protein aggregates than is induced by 20S inhibitors. These toxic misfolded protein aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR) signaling cascade and more rapidly triggers apoptosis than 20S inhibitor. The safety parameters and promising efficacy of Up284 against breast cancer lines encourages us to validate Up284 efficacy in more QNBC lines and xenografts, and examine key mechanistic and drug pharmacologic questions. This proposal will address questions critical for the development of QNBC as the lead indication for our iRPN13, Up284, and to support a pre-IND application to FDA.

乳腺癌阴性乳腺癌（QNBC），缺乏ER的表达（雌激素受体），PR （孕酮受体），HER2（人表皮生长因子受体2）和AR（雄激素受体）是 乳腺癌亚型的预后最差，QNBC不成比例地折磨非洲 美国人。它没有护理标准的治疗目标，因此有效且安全的治疗必须是 急切地寻求这种未满足的医疗需求，并解决乳腺癌预后的差异。 当前的建议是由数据升高的数据，显示蛋白酶体亚基RPN13的表达升高为 与我们 UP284抑制剂，与Karanam博士（TU）进行了强有力的合作，以及Yates博士（TU）的指导 乳腺癌亚型中的健康差异研究和戴维斯博士（Weill Cornell）。两个三重负乳房 癌症和QNBC细胞系显示出更大的蛋白酶体抑制剂的证据。但是，已获得许可 20S蛋白酶体抑制剂，例如硼替佐米，事实证明对实体瘤无效，出现了 耐药性和剂量限制毒性，包括血小板减少症和中性粒细胞减少症。 UP284有一个目标， 旨在克服许可药物在耐药性方面的局限性的结构（UP284 阻止底物识别和去泛素化，而不仅仅是三个20S催化 活动），针对实体瘤的活动不佳（UP284具有新型的螺旋结构，有证据表明 与基于肽的20S抑制剂相比，改善了药物进入肿瘤的机会） 血小板减少症和中性粒细胞减少症（与20S抑制剂不同，UP284不针对免疫蛋白酶体 由造血细胞表达，不显示这些毒性）。 UP284显示了广泛的抗癌 体外活动，包括具有强大治疗指数的QNBC线，有希望的安全性和 药效学和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 在全球范围内已申请了实现类似药物的特性的药物化学努力，并已提交专利 新颖的骨干和铅化合物。通过抑制蛋白酶体的泛素受体RPN13功能及其 相关的去泛素酶活性，UP284触发更快的积累和分子量增加 多偶联的蛋白质聚集体比20S抑制剂诱导的蛋白质聚集体。这些有毒的错误折叠蛋白 聚集体产生未解决的ER应力，激活规范展开的蛋白质反应（UPR） 与20S抑制剂相比，信号传导级联反应和更快的触发凋亡。安全参数和有希望的 UP284对乳腺癌线的功效鼓励我们在更多QNBC线上验证UP284功效 和异种移植物，并检查关键机械和药物药理问题。该建议将解决 问题对于开发QNBC作为我们的IRPN13，UP284的主要指标至关重要的问题，并支持一个 预先申请FDA。