Synthetic Strategies to Restore the Efficacy of Venetoclax in Acute Myeloid Leukemia

恢复 Venetoclax 在急性髓系白血病中的疗效的综合策略

基本信息

  • 批准号:
    10457407
  • 负责人:
  • 金额:
    $ 17.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary. Increased cell survival due to inhibited apoptosis through overexpression of anti-apoptotic BCL-2 family proteins is a hallmark of cancer that is a prominent mechanism in acute myeloid leukemia (AML), one of the deadliest human cancers. Although the FDA recently approved several new drugs for treatment of AML, these target only specific subsets of AML cases, and provide only short responses. Indeed, treatment with the BCL-2 inhibitor venetoclax (VEN), an emerging standard-of-care drug for AML, partnered with other drugs has resulted in only ~19% responses and only ~17 months median survival due to the onset of resistance. There is a clear and urgent need for more effective pharmacotherapies for AML. The BCL-2 family of proteins regulates the intrinsic apoptosis pathway, and includes both anti-apoptotic and pro-apoptotic members. The anti-apoptotic proteins, BCL-2, BCL-xL, MCL-1, BCL-w and A1, seize their pro-apoptotic partner proteins, such as BAK and BAX, via their amphipathic -helical BH3 domains. VEN is a small-molecule BH3 mimetic that is prescribed in chronic lymphocytic leukemia as well as AML, and potentially other BCL-2 dependent cancers, but its efficacy is abrogated by the development of resistance. The best characterized mechanisms of VEN resistance are upregulated expression of MCL-1 and the development of BCL-2 mutants that are no longer effectively recognized by VEN; currently, there are no clinical solutions to either of these resistance mechanisms. VEN recently demonstrated synergy in vitro and in vivo with a range of clinical drugs and advanced drug candidates that target a variety of additional proteins, with a unifying theme that the partner drug either leads to downregulation/inhibition of MCL-1 and/or upregulation of pro-apoptotic BCL-2 proteins. Since the discovery of new, highly-targeted AML drugs de novo is time- and money-intensive with no guarantees of success, we propose to utilize a polypharmacology approach, in which single drugs will be rationally designed to hit multiple targets relevant in AML, by leveraging FDA-approved drugs and those in clinical trials. Polypharmacology offers potential advantages over combination therapy, such as increased therapeutic windows and increased patient compliance. Accordingly, the solvent-exposed tetrahydropyran motif of VEN will be replaced with co- drugs that have demonstrated synergy with VEN. Similarly, we will exploit the exciting area of proteolysis targeting chimera (PROTAC) research by grafting E3 ubiquitin ligase recognition motifs onto VEN, promoting the recruitment of BCL-2 to the proteasome for degradation. This PROTAC strategy can be effective even with weaker binding ligands and thus may address the issue of resistance mutations in the BCL-2 protein. Lead compounds that potently inhibit the proliferation of VEN-sensitive and VEN-resistant AML cell lines in vitro will be evaluated in human AML xenografts. By the end of the funding period, we envisage discovering at least one VEN-based chimeric compound suitable for further preclinical evaluation in AML (and other cancers).
项目总结。通过过度表达抗凋亡基因抑制细胞凋亡,提高细胞存活率

项目成果

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CURT I CIVIN其他文献

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{{ truncateString('CURT I CIVIN', 18)}}的其他基金

Synthetic Strategies to Restore the Efficacy of Venetoclax in Acute Myeloid Leukemia
恢复 Venetoclax 在急性髓系白血病中的疗效的综合策略
  • 批准号:
    10290284
  • 财政年份:
    2021
  • 资助金额:
    $ 17.7万
  • 项目类别:
Microfluidic CAR-T Cell Processing Device
微流控CAR-T细胞处理装置
  • 批准号:
    9929262
  • 财政年份:
    2018
  • 资助金额:
    $ 17.7万
  • 项目类别:
High Efficiency Microfluidic Purification of Stem Cells to Improve Transplants
高效微流体纯化干细胞以改善移植
  • 批准号:
    8313288
  • 财政年份:
    2012
  • 资助金额:
    $ 17.7万
  • 项目类别:
Microfluidic Processing of Leukocytes for Molecular Diagnostic Testing
用于分子诊断测试的白细胞微流体处理
  • 批准号:
    8455782
  • 财政年份:
    2012
  • 资助金额:
    $ 17.7万
  • 项目类别:
MICRO RNA TARGETING OF NORMAL & LEUKEMIA STEM- PROGENITOR CELLS
正常的 MICRO RNA 靶向
  • 批准号:
    8212935
  • 财政年份:
    2011
  • 资助金额:
    $ 17.7万
  • 项目类别:
Research Administration
研究管理
  • 批准号:
    8212939
  • 财政年份:
    2011
  • 资助金额:
    $ 17.7万
  • 项目类别:
MicroRNAs regulating erythroid development
调节红细胞发育的 MicroRNA
  • 批准号:
    8010060
  • 财政年份:
    2010
  • 资助金额:
    $ 17.7万
  • 项目类别:
MicroRNAs regulating erythroid development
调节红细胞发育的 MicroRNA
  • 批准号:
    7982725
  • 财政年份:
    2008
  • 资助金额:
    $ 17.7万
  • 项目类别:
Hematopoietic Stem Cells for Transplantation
用于移植的造血干细胞
  • 批准号:
    7355791
  • 财政年份:
    2008
  • 资助金额:
    $ 17.7万
  • 项目类别:
MicroRNAs regulating erythroid development
调节红细胞发育的 MicroRNA
  • 批准号:
    7862406
  • 财政年份:
    2008
  • 资助金额:
    $ 17.7万
  • 项目类别:

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