USP7 inhibitors for the treatment of multiple myeloma

USP7抑制剂用于治疗多发性骨髓瘤

• 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
• 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

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.

摘要 多发性骨髓瘤（MM）是一种无法治愈的血液恶性肿瘤，其特征是异常增殖细胞的积聚。 骨髓（BM）中的浆细胞，其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的引入，MM患者的病情有所改善， 免疫调节剂纳入治疗方案，但仅5年仍然相当差。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发现和开发小的 泛素蛋白酶体系统的其他主要成分的分子抑制剂，包括去泛素化 (DUB)从蛋白质底物中去除降解的泛素信号的酶。DUB泛素 特异性蛋白酶7（USP 7）由于其在降解 肿瘤抑制蛋白p53。USP 7稳定MDM 2，MDM 2是负责添加泛素和驱动 p53降解。重要的是，USP 7在MM患者肿瘤细胞和MM细胞系中高度表达， 正常原代骨髓细胞。p53突变或缺失是MM的晚期事件，这表明随着MM发病率的增加， p53通过药理学抑制USP 7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USP 7抑制剂P5091对p53稳定和生长的影响 在离体和MM异种移植模型中对MM细胞的抑制作用。此外，P5091引发了 甚至在硼替佐米耐药的MM细胞中也存在凋亡。总的来说，我们的结果验证了USP 7作为治疗靶点， 毫米进一步评估USP 7作为MM靶点的潜力，并将USP 7抑制剂从实验室转移到 在床旁，我们建议利用USP 7结构指导的药物化学来开发更有效， 具有改善的药代动力学性质和体外安全性特征的选择性USP 7抑制剂。新USP 7 将使用MM的体外和体内模型以及在原代人中评价抑制剂的疗效。 样品已经组建了一个多学科团队来进行药物化学（Sara Buhrlage， Dana-Farber Cancer Institute）、生物化学和结构生物学（Sirano Dhe-Paganon，Dana-Farber Cancer 研究所），以及MM模型中的细胞和癌症生物学（Kenneth安德森和Dharminder Chauhan，Dana- Farber癌症研究所）要求在MM中重新询问USP 7。