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

四阴性乳腺癌（QNBC），缺乏ER（雌激素受体）、PR 孕激素受体（孕酮受体）、HER2（人表皮生长因子受体2）和AR（雄激素受体）是 预后最差的乳腺癌亚型，QNBC不成比例地折磨非洲人， 美国人它没有标准的治疗目标，因此必须确保有效和安全的治疗。 迫切寻求满足这一未得到满足的医疗需求，并解决乳腺癌结果的差异。 目前的建议是由数据显示蛋白酶体亚基RPN 13的表达升高引起的。 与非裔美国人种族和QNBC患者的较低生存率相关，我们的研究所针对的RPN 13 Up284抑制剂，与Karanam博士（TU）的持续密切合作，以及Yates博士（TU）的指导 健康差距研究和戴维斯博士（威尔康奈尔大学）在乳腺癌亚型。双三阴性乳腺癌 癌症和QNBC细胞系显示出对蛋白酶体抑制剂更大的脆弱性的证据。然而，许可 20S蛋白酶体抑制剂，例如硼替佐米，已被证明对实体瘤无效， 耐药性和剂量限制性毒性，包括血小板减少和中性粒细胞减少。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 阻断底物识别和去泛素化，而不仅仅是三种20 S催化剂之一， 活性），对实体瘤的活性差（Up284具有新的螺环结构，有证据表明 与基于肽的20S抑制剂相比，改善了药物对肿瘤的作用）， 血小板减少和中性粒细胞减少（与20S抑制剂不同，Up284不靶向免疫蛋白酶体 由造血细胞表达并且不显示这些毒性）。Up284显示广泛的抗癌活性 体外活性，包括针对QNBC系的活性，具有稳健的治疗指数，有希望的安全性特征， 药效学和控制异种移植肿瘤的能力。这些数据反映了我们广泛的 药物化学的努力，以实现药物样的性质和专利已提交全球范围内，以涵盖 新的骨架和先导化合物。通过抑制蛋白酶体泛素受体RPN 13的功能， 与去泛素化酶活性相关，Up284触发更快速的积累和增加的分子量 与20S抑制剂诱导的相比，多聚泛素化蛋白聚集体。这些有毒的错误折叠蛋白质 聚集体产生未解决的ER应激，激活典型的未折叠蛋白反应（UPR）， 信号级联，比20S抑制剂更快地触发细胞凋亡。安全参数和前景 Up284对乳腺癌细胞系的疗效鼓励我们在更多的QNBC细胞系中验证Up284的疗效 和异种移植，并检查关键的机制和药物药理学问题。该提案将解决 对于QNBC作为iRPN 13，Up284的主要适应症的开发至关重要的问题，并支持 向FDA提交IND前申请。

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.