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USP7 inhibitors for the treatment of multiple myeloma

USP7抑制剂用于治疗多发性骨髓瘤

基本信息

批准号：
9216507
负责人：
Sara J Buhrlage
金额：
$ 50.47万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216507
关键词：
26S proteasome Animal Model Apoptosis Automobile Driving Biochemistry Biological Biological Assay Biological Availability Biology Biophysics Blood Cells Bone Marrow Bone Marrow Cells Bortezomib Cancer Biology Caspase Cell Line Cell Proliferation Cell Survival Cells Cellular biology Chemicals Clinic Complex Crystallization Dana-Farber Cancer Institute Data Development Diagnosis Disease Dose Drug Kinetics Drug Targeting Enzymes Event Exhibits Future Growth Half-Life Hematologic Neoplasms Hour Human In Vitro Lead Link MDM2 gene Malignant Neoplasms Modeling Monitor Multiple Myeloma Mutation Names Oral Pathogenesis Patients Peptide Hydrolases Pharmaceutical Chemistry Pharmacodynamics Pharmacology Plasma Plasma Cells Production Property Proteasome Inhibitor Protein p53 Proteomics Reporting Research Resistance Resistance development Resolution Role Safety Sampling Series Signaling Protein Structure System TP53 gene Therapeutic Toxic effect Translations Treatment Protocols Tumor Suppressor Proteins Ubiquitin Validation Xenograft Model Xenograft procedure analog bench to bedside cell growth clinical investigation design drug development enzyme activity human disease immunoregulation improved in vivo in vivo Model inhibitor/antagonist interest lead series multicatalytic endopeptidase complex multidisciplinary mutant neoplastic cell next generation novel novel therapeutics outcome forecast programs prototype response small molecule inhibitor structural biology success therapeutic target tool tumor ubiquitin-specific protease validation studies

项目摘要

Abstract Multiple myeloma (MM) is an incurable hematological malignancy characterized by accumulation of abnormal plasma cells in the bone marrow (BM) which impede production of normal blood cells. The average survival of MM patients has improved in recent years as a result of introduction of proteasome inhibitors and immunomodulatory agents into treatment regimens but is still quite poor at only 5 years. FDA approval of the proteasome inhibitor bortezomib validates the ubiquitin proteasome system (UPS) as a therapeutic target for MM drug development. Recent research efforts have focused on the discovery and development of small molecule inhibitors of other major components of the ubiquitin proteasome system including deubiquitylating (DUB) enzymes which remove degradative ubiquitin signals from protein substrates. The DUB ubiquitin specific protease 7 (USP7) has garnered interest as a therapeutic target in MM due to its role in degradation of tumor suppressor protein p53. USP7 stabilizes MDM2, the protein responsible for adding ubiquitin and driving degradation of p53. Importantly, USP7 is highly expressed in MM patient tumor cells and MM cell lines versus normal primary BM cells. And mutations or deletions in p53 are late events in MM suggesting that increasing p53 via pharmacological inhibition of USP7 may offer a novel therapeutic strategy for this malignancy. We recently reported on the effects of the covalent USP7 inhibitor P5091 on p53 stabilization and growth suppressive effects against MM cells ex vivo and in MM xenograft models. Moreover, P5091 triggered apoptosis even in bortezomib-resistant MM cells. Overall, our results validate USP7 as a therapeutic target in MM. To further assess the potential of USP7 as a target in MM and move USP7 inhibitors from bench to bedside, we propose to utilize USP7 structure-guided medicinal chemistry to develop more potent and selective USP7 inhibitors with improved pharmacokinetic properties and in vitro safety profile. Novel USP7 inhibitors will be evaluated for efficacy using both in vitro and in vivo models of MM and in primary human samples. A multi-disciplinary team has been assembled to perform the medicinal chemistry (Sara Buhrlage, Dana-Farber Cancer Institute), biochemistry and structural biology (Sirano Dhe-Paganon, Dana-Farber Cancer Institute), and cell and cancer biology in MM models (Kenneth Anderson and Dharminder Chauhan, Dana- Farber Cancer Institute) required to pharmacologically interrogate USP7 in MM.

抽象的多发性骨髓瘤（MM）是一种无法治愈的血液恶性肿瘤，其特征是异常细胞的积累骨髓 (BM) 中的浆细胞阻碍正常血细胞的产生。平均存活率近年来，由于蛋白酶体抑制剂和药物的引入，多发性骨髓瘤患者的情况有所改善。免疫调节剂纳入治疗方案，但仅 5 年疗效仍然相当差。 FDA 批准蛋白酶体抑制剂硼替佐米验证了泛素蛋白酶体系统 (UPS) 作为治疗靶点 MM药物开发。最近的研究工作集中在小型的发现和开发上泛素蛋白酶体系统其他主要成分的分子抑制剂，包括去泛素化 (DUB) 酶，可从蛋白质底物中去除降解泛素信号。 DUB 泛素特异性蛋白酶 7 (USP7) 作为 MM 的治疗靶点引起了人们的兴趣，因为它在降解肿瘤抑制蛋白p53。 USP7 稳定 MDM2，该蛋白负责添加泛素并驱动 p53 的降解。重要的是，与 MM 患者肿瘤细胞和 MM 细胞系相比，USP7 在 MM 患者肿瘤细胞和 MM 细胞系中高表达正常原代骨髓细胞。 p53 的突变或缺失是 MM 的晚期事件，表明增加 p53 通过药理抑制 USP7 可能为这种恶性肿瘤提供一种新的治疗策略。我们最近报道了共价 USP7 抑制剂 P5091 对 p53 稳定和生长的影响对离体 MM 细胞和 MM 异种移植模型中的抑制作用。此外，P5091触发即使在硼替佐米耐药的 MM 细胞中也会发生细胞凋亡。总体而言，我们的结果验证了 USP7 作为治疗靶点毫米。进一步评估 USP7 作为 MM 靶点的潜力，并将 USP7 抑制剂从实验室转移到在临床上，我们建议利用 USP7 结构指导的药物化学来开发更有效、更有效的药物。选择性 USP7 抑制剂，具有改善的药代动力学特性和体外安全性。小说USP7 将使用 MM 的体外和体内模型以及原代人类模型来评估抑制剂的功效样品。已组建了一个多学科团队来执行药物化学（Sara Buhrlage，丹娜—法伯癌症研究所），生物化学和结构生物学（Sirano Dhe-Paganon，丹娜—法伯癌症研究所）研究所），以及 MM 模型中的细胞和癌症生物学（Kenneth Anderson 和 Dharminder Chauhan，Dana- Farber 癌症研究所）需要对 MM 中的 USP7 进行药理学研究。