Chaperone-Mediated Protein Degradation of Bcl-xL and Bcl-2

分子伴侣介导的 Bcl-xL 和 Bcl-2 蛋白质降解

• 批准号: 10599452
• 负责人: Marina Y Konopleva
• 金额: $ 4.7万
• 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/10599452
• 关键词: Acute Myelocytic Leukemia; Acute T Cell Leukemia; Adverse effects; Antineoplastic Agents; Apoptotic; BCL2 gene; BCL2L1 gene; Biological Assay; Blood Platelets; Cancer Relapse; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical Trials; Coupled; Data; Dose-Limiting; Drug resistance; Evaluation; Goals; In Vitro; Lead; Malignant Neoplasms; Mediating; Molecular Chaperones; Names; Neoplasm Metastasis; Pharmaceutical Preparations; Property; Protac; Protein Family; Research; Series; Technology; Therapeutic; Thrombocytopenia; Tissues; Toxic effect; base; bcl-xlong protein; cancer type; chemotherapy; design; drug discovery; improved; in vivo; inhibitor; innovation; leukemia; mouse model; novel strategies; patient derived xenograft model; preclinical efficacy; prevent; protein degradation; recruit; senescence; small molecule; targeted cancer therapy; targeted treatment; tumor xenograft; ubiquitin-protein ligase

Project Summary 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.

项目概要 靶向抗凋亡 Bcl-2 家族蛋白是一种有前途的癌症治疗策略，并且已被证实 Bcl-2 选择性抑制剂 Venetoclax 经 FDA 批准用于治疗慢性淋巴细胞白血病 白血病（CLL）和急性髓性白血病（AML）。鉴于 Bcl-xL 对许多人的重要性有据可查 癌症类型，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 抗性，Bcl-xL 已成为经过验证的最佳癌症靶点之一。不幸的是，目标和剂量 限制与 Bcl-xL 抑制相关的血小板毒性已阻止 Bcl-xL 抑制剂在 诊所。为了规避这种毒性，我们应用了蛋白水解靶向嵌合体 (PROTAC) 技术 设计将 Bcl-xL 靶向 E3 连接酶进行降解的小分子。我们的假设是 Bcl-xL 降解 PROTAC（称为 Bcl-Ps）旨在招募在血小板中最低表达的 E3 连接酶，以用于 与相比，Bcl-xL 的靶向降解将降低血小板毒性并提高抗肿瘤活性 其相应的 Bcl-xL 抑制剂。这一假设得到了我们强有力的初步结果的支持，包括 T-ALL 患者来源的异种移植 (PDX) 小鼠模型和其他肿瘤异种移植小鼠的体内疗效数据 模型。此外，我们的 Bcl-P 也是有效的衰老剂，可以选择性杀死衰老细胞 (SnC)， 因为 SnC 也依赖 Bcl-xL 生存。化疗引起的 SnCs 的清除被认为是 预防或减少化疗药物许多短期和长期不良反应的新策略， 以及癌症的复发和转移。总的来说，这些发现表明 Bcl-P 优于 传统的 Bcl-xL 抑制剂作为抗癌剂。该应用的目标是： (1) 优化 Bcl-P 提高效力、选择性、类药特性和体内功效； (2) 通过a评估新的Bcl-Ps 系列体外和体内测定； (3) 评估先导 Bcl-P 在 T-ALL PDX 模型中的临床前疗效。 该项目完成后，我们的目标是生产能够在 T-临床试验中进一步评估的 Bcl-P。 ALL，一种侵袭性白血病，目前尚无靶向治疗方法。