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凋亡，从而增加细胞存活 BCL-2家族蛋白是癌症的标志，其是急性髓性白血病（AML）中的突出机制， 是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。事实上，治疗 BCL-2抑制剂venetoclax（VEN）是一种新兴的AML标准治疗药物， 药物治疗仅导致~19%的反应，中位生存期仅~17个月， 阻力对于AML的更有效的药物疗法存在明确且迫切的需求。 BCL-2蛋白家族调节内在凋亡途径，并且包括抗凋亡和抗凋亡调节。 和促凋亡成员。抗凋亡蛋白BCL-2、BCL-xL、MCL-1、BCL-w和A1抓住它们的作用。 促凋亡伴侣蛋白，如BAK和BAX，通过它们的两亲性β-螺旋BH 3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AML， 其他BCL-2依赖性癌症，但其疗效因耐药性的发展而消失。最好的 VEN耐药的特征性机制是MCL-1的表达上调， VEN不再有效识别的BCL-2突变体;目前，没有临床解决方案， 这两种抵抗机制。 VEN最近在体外和体内显示出与一系列临床药物和先进药物的协同作用 靶向多种其他蛋白质的候选药物，具有一个统一的主题， 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药物从头是时间和金钱密集型的，没有成功的保证，我们 我建议利用多药理学的方法，其中单一药物将被合理设计，以打击多个 通过利用FDA批准的药物和临床试验中的药物，多元药理学 提供了优于联合治疗的潜在优势，例如增加的治疗窗口和增加的 患者依从性。因此，VEN的暴露于溶剂的四氢吡喃基序将被共- 已证明与VEN协同作用的药物。同样，我们将探索蛋白质水解的激动人心的领域， 通过将E3泛素连接酶识别基序移植到VEN上，促进靶向嵌合体（PROTAC）研究， BCL-2向蛋白酶体的募集以进行降解。这种PROTAC策略即使在 较弱的结合配体，因此可以解决BCL-2蛋白中的抗性突变问题。铅 在体外有效抑制VEN敏感性和VEN抗性AML细胞系增殖的化合物将 在人AML异种移植物中进行评价。到资助期结束时，我们设想至少发现一个 基于VEN的嵌合化合物适合于AML（和其他癌症）的进一步临床前评价。

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).