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).
项目摘要。通过过表达抗凋亡蛋白抑制细胞凋亡,从而提高细胞存活率
BCL-2家族蛋白是癌症的标志,而癌症是急性髓系白血病(AML)的重要机制。
人类最致命的癌症之一。尽管FDA最近批准了几种治疗糖尿病的新药
对于急性髓系白血病,这些措施只针对急性髓系白血病病例的特定子集,并且只提供简短的反应。的确,治疗
通过bcl2抑制剂VEN(VEN),一种治疗AML的新兴标准药物,与其他
药物仅导致~19%的反应,由于发病,中位生存期仅为~17个月
抵抗。对于急性髓系白血病来说,显然迫切需要更有效的药物治疗方法。
BCL-2家族蛋白调控固有的细胞凋亡途径,包括抗细胞凋亡
以及支持细胞凋亡的成员。BCL-2、BCL-XL、MCL-1、BCL-W和A1等抗细胞凋亡蛋白
促凋亡伙伴蛋白,如BAK和BAX,通过它们的两亲性-螺旋BH3结构域。Ven是一个
小分子BH3模拟物,用于慢性淋巴细胞白血病和急性髓细胞白血病,并可能
其他依赖bcl-2的癌症,但其疗效因耐药性的发展而丧失。最好的
VEN耐药的机制主要是上调MCL-1的表达和血管内皮细胞的发生发展
Bcl2突变体不再被VEN有效识别;目前,还没有临床解决方案
这两种抵抗机制中的任何一种。
Ven最近在体外和体内展示了与一系列临床药物和先进药物的协同作用
以多种额外蛋白质为靶点的候选药物,具有一个统一的主题,合作药物要么导致
下调/抑制MCL-1和/或上调促凋亡的BCL-2蛋白。自从发现了
新的、高度靶向的急性髓细胞白血病药物的新药是耗时和金钱密集型的,不能保证成功,我们
建议使用多种药理学方法,其中单一药物将被合理设计以达到多种药物
通过利用FDA批准的药物和临床试验中的药物,达到与AML相关的靶点。多元药理学
提供了比联合治疗更大的潜在优势,例如增加了治疗窗口和
患者依从性。因此,暴露在溶剂中的VEN的四氢吡喃基序将被co-
已证明与VEN有协同作用的药物。同样,我们将开发令人兴奋的蛋白质分解领域。
靶向嵌合体(PROTAC)研究通过将E3泛素连接酶识别基序嫁接到VEN上,促进
Bcl-2在蛋白酶体中的募集以进行降解。这种PROTAC策略即使在
较弱的结合配体,从而可能解决bcl2蛋白的耐药性突变问题。铅
在体外有效抑制VEN敏感和耐药AML细胞系增殖的化合物将
在人急性髓系白血病异种移植中进行评估。到资助期结束时,我们预计至少会发现一个
基于VEN的嵌合化合物,适用于AML(和其他癌症)的进一步临床前评估。
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:
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High Efficiency Microfluidic Purification of Stem Cells to Improve Transplants
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8313288 - 财政年份:2012
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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
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8212935 - 财政年份:2011
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