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：
10290284
负责人：
CURT I CIVIN
金额：
$ 21.67万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10290284
关键词：
Acute Myelocytic Leukemia Adamantane Address Apoptosis Apoptotic Area BAX gene BCL-2 Protein BCL1 Oncogene BCL2 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 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/antagonist interest member mimetics multicatalytic endopeptidase complex mutant novel therapeutics overexpression pharmacokinetics and pharmacodynamics pharmacophore pre-clinical preclinical evaluation pro-apoptotic protein public health relevance 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).

项目摘要通过抗凋亡蛋白的过度表达抑制细胞凋亡，从而提高细胞存活率。 BCL-2 家族蛋白是癌症的一个标志，是急性髓系白血病 (AML) 的一个重要机制，尽管 FDA 最近批准了几种治疗癌症的新药。 AML，这些药物仅针对 AML 病例的特定子集，并且仅提供短期治疗。与 BCL-2 抑制剂 venetoclax (VEN) 合作，这是一种新兴的 AML 标准治疗药物，与其他公司合作药物仅产生约 19% 的反应，并且由于出现显然，迫切需要更有效的 AML 药物治疗。 BCL-2 蛋白家族调节内在细胞凋亡途径，包括抗细胞凋亡和抗凋亡蛋白 BCL-2、BCL-xL、MCL-1、BCL-w 和 A1 抓住它们的作用。促凋亡伙伴蛋白，例如 BAK 和 BAX，通过其两亲性 α-螺旋 BH3 结构域是一种。小分子 BH3 模拟物，用于治疗慢性淋巴细胞白血病和 AML，并且有可能其他 BCL-2 依赖性癌症，但其疗效会因耐药性的产生而被消除。 VEN 抗性的特征机制是 MCL-1 表达上调以及目前VEN不再有效识别的BCL-2突变体，尚无临床解决方案；这些抵抗机制中的任何一个。 VEN最近在体外和体内证明了与一系列临床药物和先进药物的协同作用针对多种其他蛋白质的候选药物，具有统一的主题，即伙伴药物要么导致自从发现以来，MCL-1 的下调/抑制和/或促凋亡 BCL-2 蛋白的上调。新的、高度靶向的 AML 药物从头开始是时间和金钱密集型的，并且不能保证成功，我们提议利用多药理学方法，其中单一药物将被合理设计以作用于多种通过利用 FDA 批准的药物和临床试验中的药物，确定与 AML 相关的目标。与联合疗法相比具有潜在优势，例如增加治疗窗和增加因此，VEN 中暴露于溶剂的四氢吡喃基序将被 co- 取代。同样，我们将开发令人兴奋的蛋白水解领域通过将E3泛素连接酶识别基序移植到VEN上，进行靶向嵌合体（PROTAC）研究，促进将 BCL-2 募集至蛋白酶体进行降解，这种 PROTAC 策略甚至可以有效。较弱的结合配体，因此可能解决 BCL-2 先导蛋白中的耐药突变问题。在体外有效抑制 VEN 敏感和 VEN 抗性 AML 细胞系增殖的化合物将在人类 AML 异种移植物中进行评估，到资助期结束时，我们预计会发现至少一种。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。