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
- 来源:
- 关键词:Acute Myelocytic LeukemiaAdamantaneAddressApoptosisApoptoticAreaBAX geneBCL-2 ProteinBCL1 OncogeneBCL2 geneBCL2L1 geneBCL2L11 geneBH3 DomainBindingBiologicalBiological AssayCardiotoxicityCell LineCell SurvivalCellsChemotherapy-Oncologic ProcedureChimera organismChronic Lymphocytic LeukemiaClinicalClinical TrialsCombined Modality TherapyDevelopmentDiagnosisDown-RegulationDrug DesignDrug InteractionsEnsureFDA approvedFLT3 geneFundingGoalsHematopoietic NeoplasmsHistone DeacetylaseHumanHydrophobicityIn VitroLeadLengthLigand BindingLigandsLinkMAP2K1 geneMCL1 geneMDM2 geneMalignant NeoplasmsModelingModificationOutcomePersonsPharmaceutical PreparationsPharmacotherapyProtacProtein FamilyProteinsRUNX3 geneRegimenReportingResearchResistanceResistance developmentSisterSolid NeoplasmSolventsStructureSurvival RateTechnologyTestingThalidomideTherapeuticThrombocytopeniaTimeTissuesUp-RegulationWorkXenograft ModelXenograft procedureacute myeloid leukemia cellanalogbasechimera drugcompliance behaviordesigndrug candidateeffective therapyimprovedin vivoinhibitorinterestmembermimeticsmulticatalytic endopeptidase complexmutantnovel therapeuticsoverexpressionpharmacokinetics and pharmacodynamicspharmacophorepre-clinicalpreclinical evaluationpro-apoptotic proteinpublic health relevancerational designrecruitresistance mechanismresistance mutationresponsesmall moleculestandard of caresuccesssynergismtargeted treatmentubiquitin-protein ligase
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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{{ 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:
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:
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