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 (PROTAC) 是异双功能分子，由通过接头连接的两个配体组成，使它们能够同时与 E3 连接酶和目标蛋白 (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、细胞选择性差和渗透性低。 AS1411 是一种抗肿瘤适体，特异性识别膜-核穿梭核仁素 (NCL)。在这里，我们通过锚定 NCL-MDM2 复合物将 AS1411 重新用作 E3 连接酶小鼠双分钟 2 同源物 (MDM2) 的配体。然后，我们通过将 AS1411 与“不可成药”致癌 STAT3、c-Myc、p53-R175H 和 AR-V7 的大分子量配体缀合，构建了基于 AS1411-NCL-MDM2 的 PROTAC (ANM-PROTAC)。我们证明 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，并表现出优异的抗肿瘤活性，且无全身毒性。这是一种具有内置肿瘤靶向和细胞穿透能力的 PROTAC。