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Bcl-2家族蛋白是一种很有前途的治疗癌症的策略，并已被证实