Inhibition of Bcl-xL by Targeted Degradation

通过靶向降解抑制 Bcl-xL

基本信息

  • 批准号:
    10133018
  • 负责人:
  • 金额:
    $ 50.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Marina Y Konopleva其他文献

Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML
阿扎胞苷、维奈托克和 Gilteritinib 治疗新诊断和复发或难治性 FLT3 突变 AML
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    45.3
  • 作者:
    N. Short;N. Daver;C. Dinardo;T. Kadia;L. Nasr;W. Macaron;M. Yilmaz;G. Borthakur;G. Montalban;G. Garcia;G. Issa;K. Chien;E. Jabbour;Cedric Nasnas;Xuelin Huang;W. Qiao;J. Matthews;Christopher J Stojanik;K. Patel;R. Abramova;J. Thankachan;Marina Y Konopleva;H. Kantarjian;F. Ravandi
  • 通讯作者:
    F. Ravandi

Marina Y Konopleva的其他文献

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{{ truncateString('Marina Y Konopleva', 18)}}的其他基金

Administrative Core
行政核心
  • 批准号:
    10931064
  • 财政年份:
    2023
  • 资助金额:
    $ 50.57万
  • 项目类别:
Defining the novel cancer testis antigen HSPA1L as immunotherapeutic target in AML
将新型癌症睾丸抗原 HSPA1L 定义为 AML 的免疫治疗靶点
  • 批准号:
    10625516
  • 财政年份:
    2022
  • 资助金额:
    $ 50.57万
  • 项目类别:
Defining the novel cancer testis antigen HSPA1L as immunotherapeutic target in AML
将新型癌症睾丸抗原 HSPA1L 定义为 AML 的免疫治疗靶点
  • 批准号:
    10433726
  • 财政年份:
    2022
  • 资助金额:
    $ 50.57万
  • 项目类别:
Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
  • 批准号:
    10737840
  • 财政年份:
    2020
  • 资助金额:
    $ 50.57万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 50.57万
  • 项目类别:
Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
  • 批准号:
    10378075
  • 财政年份:
    2020
  • 资助金额:
    $ 50.57万
  • 项目类别:
Inhibition of Bcl-xL by Targeted Degradation
通过靶向降解抑制 Bcl-xL
  • 批准号:
    10644990
  • 财政年份:
    2020
  • 资助金额:
    $ 50.57万
  • 项目类别:
Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen
使用 BCL-2 抑制剂 Venetoclax 和优化的 10 天地西他滨方案靶向高危 AML 和 MDS 中的细胞凋亡
  • 批准号:
    10415997
  • 财政年份:
    2019
  • 资助金额:
    $ 50.57万
  • 项目类别:
Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen
使用 BCL-2 抑制剂 Venetoclax 和优化的 10 天地西他滨方案靶向高危 AML 和 MDS 中的细胞凋亡
  • 批准号:
    10654631
  • 财政年份:
    2019
  • 资助金额:
    $ 50.57万
  • 项目类别:
Targeting mitochondrial complex I in acute lymphoblastic leukemia
靶向急性淋巴细胞白血病中的线粒体复合物 I
  • 批准号:
    9815737
  • 财政年份:
    2019
  • 资助金额:
    $ 50.57万
  • 项目类别:

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