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：
CURT I CIVIN
金额：
$ 17.7万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
https://reporter.nih.gov/project-details/10457407
关键词：
Acute Myelocytic Leukemia Adamantane Address Apoptosis Apoptotic Area BAX gene BCL-2 Protein BCL1 Oncogene BCL2 gene BCL2L1 gene BCL2L11 gene BH3 Domain Binding Biological Biological Assay Cardiotoxicity Cell Line Cell Survival Cells Chemotherapy-Oncologic Procedure Chimera organism Chronic Lymphocytic Leukemia Clinical Clinical Trials Combined Modality Therapy Development Diagnosis Down-Regulation Drug Design Drug Interactions Ensure FDA approved FLT3 gene Funding Goals Hematopoietic Neoplasms Histone Deacetylase Human Hydrophobicity In Vitro Lead Length Ligand Binding Ligands Link MAP2K1 gene MCL1 gene MDM2 gene Malignant Neoplasms Modeling Modification Outcome Persons Pharmaceutical Preparations Pharmacotherapy Protac Protein Family Proteins RUNX3 gene Regimen Reporting Research Resistance Resistance development Sister Solid Neoplasm Solvents Structure Survival Rate Technology Testing Thalidomide Therapeutic Thrombocytopenia Time Tissues Up-Regulation Work Xenograft Model Xenograft procedure acute myeloid leukemia cell analog base chimera drug compliance behavior design drug candidate effective therapy improved in vivo inhibitor interest member mimetics multicatalytic endopeptidase complex mutant novel therapeutics overexpression pharmacokinetics and pharmacodynamics pharmacophore pre-clinical preclinical evaluation pro-apoptotic protein public health relevance rational design recruit resistance mechanism resistance mutation response small molecule standard of care success synergism targeted treatment ubiquitin-protein ligase

Acute Myelocytic Leukemia Adamantane Address Apoptosis Apoptotic Area BAX gene BCL-2 Protein BCL1 Oncogene BCL2 gene BCL2L1 gene BCL2L11 gene BH3 Domain Binding Biological Biological Assay Cardiotoxicity Cell Line Cell Survival Cells Chemotherapy-Oncologic Procedure Chimera organism Chronic Lymphocytic Leukemia Clinical Clinical Trials Combined Modality Therapy Development Diagnosis Down-Regulation Drug Design Drug Interactions Ensure FDA approved FLT3 gene Funding Goals Hematopoietic Neoplasms Histone Deacetylase Human Hydrophobicity In Vitro Lead Length Ligand Binding Ligands Link MAP2K1 gene MCL1 gene MDM2 gene Malignant Neoplasms Modeling Modification Outcome Persons Pharmaceutical Preparations Pharmacotherapy Protac Protein Family Proteins RUNX3 gene Regimen Reporting Research Resistance Resistance development Sister Solid Neoplasm Solvents Structure Survival Rate Technology Testing Thalidomide Therapeutic Thrombocytopenia Time Tissues Up-Regulation Work Xenograft Model Xenograft procedure acute myeloid leukemia cell analog base chimera drug compliance behavior design drug candidate effective therapy improved in vivo inhibitor interest member mimetics multicatalytic endopeptidase complex mutant novel therapeutics overexpression pharmacokinetics and pharmacodynamics pharmacophore pre-clinical preclinical evaluation pro-apoptotic protein public health relevance rational design recruit resistance mechanism resistance mutation response small molecule standard of care success synergism targeted treatment ubiquitin-protein ligase

展开

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。通过过度表达抗凋亡，由于抑制凋亡而增加的细胞存活率增加 Bcl-2家族蛋白是癌症的标志，是急性髓样白血病（AML）的重要机制，最致命的人类癌症之一。尽管FDA最近批准了几种用于治疗的新药 AML，这些仅针对AML病例的特定子集，仅提供简短的响应。确实，治疗与AML的新兴标准药物BCL-2抑制剂Venetoclax（VEN）与其他合作药物仅产生约19％的反应，并且由于发作而仅产生约17个月的中位生存期反抗。明显而迫切需要对AML进行更有效的药物治疗。 Bcl-2蛋白质家族调节固有凋亡途径，包括抗凋亡和促凋亡的成员。抗凋亡蛋白Bcl-2，Bcl-XL，Mcl-1，Bcl-W和A1 促凋亡的伴侣蛋白，例如Bak和Bax，通过其两亲性BH3域。 Ven是小分子BH3模拟物在慢性淋巴细胞性白血病和AML中规定，并可能有可能其他依赖性BCl-2癌症，但其有效性被抵抗的发展所消除。最好的 VEN电阻的特征机制是MCL-1的更新表达和开发不再被VEN有效识别的Bcl-2突变体；目前，没有临床解决方案这些抗性机制中的任何一个。 VEN最近证明了体外和体内的协同作用，并具有一系列临床药物和晚期药物针对各种其他蛋白质的候选人，其统一主题是合作伙伴药物会导致的 MCL-1的下调/抑制和/或促凋亡Bcl-2蛋白的上调。自从发现从头开始，新的，高度靶向的AML药物是时间和货币密集型的，无法保证成功，我们利用多种药理学方法的提议，其中将单一药物合理设计为击中多个药物通过利用FDA批准的药物和临床试验中的药物相关的目标。多药理学提供了与组合疗法相比的潜在优势，例如增加的治疗窗口和增加患者合规性。根据溶液暴露的四氢吡喃基序，将被共同代替与VEN有协同作用的药物。同样，我们将利用令人兴奋的蛋白水解领域通过将E3泛素连接酶识别基序靶向嵌合体（Protac）研究，促进将Bcl-2募集到蛋白酶体中以降解。这种Protac策略即使是有效的较弱的结合配体可能会解决Bcl-2蛋白中抗性突变的问题。带领可能抑制体外敏感和抗Ven敏感性AML细胞系的增殖的化合物将在人类AML Xenographics中进行评估。到资金期结束时，我们设想发现至少一个基于VEN的嵌合化合物适用于AML（和其他癌症）中进一步的临床前评估。