Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China; Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
Cell Chem Biol. 2024 Jul 18;31(7):1290-1304.e7. doi: 10.1016/j.chembiol.2024.03.011. Epub 2024 Apr 23.
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.
蛋白水解靶向嵌合体（PROTACs）是由两个配体通过连接子连接而成的杂双功能分子，使其能够同时与 E3 连接酶和靶蛋白（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、细胞选择性差和通透性低。AS1411 是一种特异性识别核穿梭核仁素（NCL）的抗肿瘤适体。在这里，我们通过锚定 NCL-MDM2 复合物，将 AS1411 重新用作 E3 连接酶小鼠双微体 2 同源物（MDM2）的配体。然后，我们通过将 AS1411 与“不可成药”的致癌 STAT3、c-Myc、p53-R175H 和 AR-V7 的大分子量配体偶联，构建了一种基于 AS1411-NCL-MDM2 的 PROTAC（ANM-PROTAC）。我们表明，ANM-PROTAC 能够有效地穿透肿瘤细胞，招募 MDM2 并降解 POI。ANM-PROTAC 实现了肿瘤选择性分布，并表现出优异的抗肿瘤活性，而没有全身毒性。这是一种具有内置肿瘤靶向和细胞穿透能力的 PROTAC。
