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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

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