Synthetic Strategies to Restore the Efficacy of Venetoclax in Acute Myeloid Leukemia

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。

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).