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)是一种以异常堆积为特征的不可治愈的血液系统恶性肿瘤 骨髓(BM)中阻碍正常血细胞产生的浆细胞。小鼠的平均存活率 近年来，多发性骨髓瘤患者由于引入蛋白酶体抑制剂和 免疫调节剂进入治疗方案，但在仅5年的时间里仍然相当差。FDA批准了该产品 蛋白酶体抑制剂Bortezomib验证泛素蛋白酶体系统(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发展小的 泛素蛋白酶体系统其他主要成分的分子抑制剂，包括脱泛素化作用 (DUB)从蛋白质底物中去除降解泛素信号的酶。配音泛素 特异性蛋白水解酶7(USP7)作为多发性骨髓瘤的治疗靶点，因其在多发性骨髓瘤中的降解作用而备受关注。 肿瘤抑制蛋白P53。USP7稳定MDM2，这种蛋白质负责增加泛素和驱动 P53的降解。重要的是，USP7在多发性骨髓瘤患者肿瘤细胞和多发性骨髓瘤细胞系中高表达 正常原代BM细胞。而P53的突变或缺失是多发性骨髓瘤的晚期事件，表明增加 P53通过对USP7的药理抑制可能为这种恶性肿瘤提供一种新的治疗策略。我们 共价USP7抑制剂P5091对P53稳定和生长影响的研究进展 体外和MM异种移植模型中对MM细胞的抑制作用。此外，P5091触发了 甚至在对硼替佐米耐药的MM细胞中也发生了凋亡。总体而言，我们的结果验证了USP7作为治疗靶点在 进一步评估USP7作为多发性骨髓瘤靶点的潜力，并将USP7抑制剂从BASE转移到 床边，我们建议利用USP7结构引导的药物化学来开发更有效的和 具有改善的药代动力学特性和体外安全性的选择性USP7抑制剂。新奇的USP7 将使用多发性骨髓瘤的体外和体内模型以及原代人类来评估这些抑制剂的有效性 样本。已经组建了一个多学科团队来执行药物化学(Sara Buhrlage， Dana-Farber癌症研究所)，生物化学和结构生物学(Sirano dhe-Paganon，Dana-Farber癌症 以及MM模型中的细胞和癌症生物学(Kenneth Anderson和Dharminder Chauhan，Dana- 法伯癌症研究所)被要求对MM的USP7进行药理学讯问。