Inhibition of Bcl-xL by Targeted Degradation

通过靶向降解抑制 Bcl-xL

• 批准号: 10133018
• 负责人: Marina Y Konopleva
• 金额: $ 50.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10133018
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Adverse effects; Antineoplastic Agents; Apoptosis; Apoptotic; BCL2 gene; Biological Assay; Blood Platelets; Cancer Relapse; Cells; Chemoresistance; Chemotherapy and/or radiation; Chronic Lymphocytic Leukemia; Clinic; Clinical Trials; Coupled; Cytometry; Data; Dependence; Development; Dexamethasone; Dose-Limiting; Doxorubicin; Drug Kinetics; Drug resistance; Evaluation; Exhibits; Formulation; Goals; Human; In Vitro; Lead; Leukemia Acute Lymphoblastic Chemotherapy; Ligands; MCL1 gene; Malignant Neoplasms; Mediating; Mus; Names; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Property; Protac; Protein Family; Proteins; Refractory; Relapse; Research; Resistance; Role; Series; Specificity; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Thrombocytopenia; Tissues; Toxic effect; Treatment Efficacy; Vincristine; Water; analog; anti-cancer; asparaginase; base; bcl-xlong protein; cancer cell; cancer therapy; cancer type; chemotherapy; clinical application; clinically relevant; design; drug discovery; efficacy evaluation; improved; in vitro Assay; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; leukemia; mouse model; novel; novel strategies; patient derived xenograft model; preclinical efficacy; prevent; protein degradation; recruit; scale up; senescence; small molecule; standard of care; success; targeted cancer therapy; targeted treatment; tumor initiation; tumor xenograft; ubiquitin-protein ligase

Targeting the anti-apoptotic Bcl-2 family proteins is a promising therapeutic strategy for cancer and has been validated by the FDA approval of the Bcl-2 selective inhibitor, venetoclax, for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Given the well-documented importance of Bcl-xL to many types of cancers, including most T-cell acute lymphoblastic leukemia (T-ALL), and its contribution to drug resistance, Bcl-xL has become one of the best validated cancer targets. Unfortunately, the on-target and dose- limiting platelet toxicity associated with the inhibition of Bcl-xL has prevented the use of Bcl-xL inhibitors in the clinic. To circumvent this toxicity, we have applied the Proteolysis Targeting Chimera (PROTAC) technology to design small-molecules that target Bcl-xL to E3 ligases for degradation. Our hypothesis is that Bcl-xL degrading PROTACs (named as Bcl-Ps) designed to recruit an E3 ligase that is minimally expressed in platelets for the targeted degradation of Bcl-xL will have reduced platelet toxicity and improved antitumor activity compared with their corresponding Bcl-xL inhibitors. This hypothesis is supported by our strong preliminary results, including in vivo efficacy data in T-ALL patient-derived xenograft (PDX) mouse models and other tumor xenograft mouse models. In addition, our Bcl-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs), because SnCs also rely on Bcl-xL for survival. Clearance of chemotherapy-induced SnCs is considered as a novel strategy to prevent or reduce many short- and long-term adverse effects of the chemotherapeutic drugs, as well as cancer relapse and metastasis. Collectively, these findings suggest that Bcl-Ps are superior to conventional Bcl-xL inhibitors as anticancer agents. The goal of this application is to: (1) optimize Bcl-Ps for improved potency, selectivity, drug-like properties, and in vivo efficacy; (2) evaluate the new Bcl-Ps through a series of in vitro and in vivo assays; and (3) evaluate the preclinical efficacy of lead Bcl-Ps in T-ALL PDX models. Upon completion of this project, we aim to produce Bcl-Ps amenable to further evaluation in clinical trials for T- ALL, an aggressive leukemia that currently has no targeted therapies.

靶向抗凋亡的Bcl-2家族蛋白是一种有前途的癌症治疗策略，一直是 通过BCL-2选择性抑制剂Venetoclax的FDA批准来验证慢性淋巴细胞的治疗 白血病（CLL）和急性髓样白血病（AML）。考虑到BCL-XL对许多人的重要性 癌症的类型，包括大多数T细胞急性淋巴细胞白血病（T-All）及其对药物的贡献 阻力，BCL-XL已成为最佳验证癌症靶标之一。不幸的是，目标和剂量 - 限制与抑制BCL-XL相关的血小板毒性已阻止使用BCL-XL抑制剂 诊所。为了避免这种毒性，我们已经将靶向嵌合技术（Protac）技术应用于 设计将BCl-XL靶向E3连接酶的小分子以降解。我们的假设是BCL-XL降解 Protac（称为BCL-PS）旨在募集E3连接酶，该连接酶在血小板中最少表达 BCL-XL的靶向降解将降低血小板毒性，并改善抗肿瘤活性 它们相应的BCL-XL抑制剂。我们的强大初步结果支持了这一假设 T-ALL患者衍生异种移植（PDX）小鼠模型和其他肿瘤异种移植小鼠中的体内功效数据 型号。此外，我们的BCL-PS也是有效的鼻溶剂，可以选择性地杀死衰老细胞（SNC），， 因为SNC也依靠BCL-XL来生存。化学疗法诱导的SNC的清除被认为是 预防或减少化学治疗药物的许多短期和长期不良影响的新策略， 以及癌症复发和转移。总的来说，这些发现表明BCL-PS优于 常规的BCl-XL抑制剂作为抗癌剂。该应用程序的目的是：（1）优化BCL-PS 提高效力，选择性，类似药物的特性和体内功效； （2）通过A评估新的BCL-PS 一系列体外和体内测定； （3）评估T-ALL PDX模型中铅BCL-PS的临床前功效。 该项目完成后，我们旨在生产可符合的BCL-PS，以进一步评估T-的临床试验 所有人，目前尚无靶向疗法的积极性白血病。