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: 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
• 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

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， 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 AML，这些仅针对 AML 病例的特定子集，并且仅提供简短的响应。确实，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 反抗。显然，迫切需要更有效的 AML 药物疗法。 BCL-2 蛋白家族调节内在细胞凋亡途径，包括抗细胞凋亡和 和促凋亡成员。抗凋亡蛋白 BCL-2、BCL-xL、MCL-1、BCL-w 和 A1 抓住它们的 促凋亡伴侣蛋白，例如 BAK 和 BAX，通过其两亲性 α-螺旋 BH3 结构域。 VEN 是一个 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，但其功效会因耐药性的产生而被消除。最好的 VEN 抗性的特征机制是 MCL-1 表达上调以及 VEN 不再有效识别的 BCL-2 突变体；目前尚无临床解决方案 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 MCL-1 的下调/抑制和/或促凋亡 BCL-2 蛋白的上调。自从发现 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。多药理学 与联合疗法相比具有潜在优势，例如增加治疗窗和增加 患者的依从性。因此，VEN 暴露于溶剂的四氢吡喃基序将被替换为共- 已证明与 VEN 具有协同作用的药物。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。即使在以下情况下，该 PROTAC 策略也可以有效 较弱的结合配体，因此可能解决 BCL-2 蛋白中的耐药突变问题。带领 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。