Repurposing AS1411 for constructing ANM-PROTACs

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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Abstract

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for “undruggable” oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

Abstract Image

Abstract Image

重新利用 AS1411 构建 ANM-PROTAC
蛋白水解靶向嵌合体(PROTACs)是由两个配体通过连接体连接而成的异功能分子,使其能够同时与E3连接酶和感兴趣的蛋白质(POI)结合,并触发POI的蛋白酶体降解。PROTAC 的局限性包括缺乏有效的 E3 配体、细胞选择性差和渗透性低。AS1411 是一种特异性识别膜-核穿梭核蛋白(NCL)的抗肿瘤配体。在这里,我们通过锚定 NCL-MDM2 复合物,将 AS1411 重新用作 E3 连接酶小鼠双分 2 同源物(MDM2)的配体。然后,我们通过将 AS1411 与 "不可药用 "致癌物质 STAT3、c-Myc、p53-R175H 和 AR-V7 的大分子量配体共轭,构建了基于 AS1411-NCL-MDM2 的 PROTAC(ANM-PROTAC)。我们的研究表明,ANM-PROTAC 能有效穿透肿瘤细胞,招募 MDM2 并降解 POIs。ANM-PROTAC 实现了肿瘤选择性分布,并表现出卓越的抗肿瘤活性,且无全身毒性。这是一种具有肿瘤靶向和细胞穿透能力的 PROTAC。
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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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