第二军医大学Chunquan Sheng研究团队近日取得一项新成果。经过不懈努力，他们开发出用于乳腺癌肿瘤特异性靶向的适体-PROTAC缀合物(APCs)。2021年7月9日，国际知名学术期刊《德国应用化学》发表了这一成果。

据介绍，开发针对蛋白降解靶向嵌合体（PROTACs）是针对靶向蛋白降解一种有前景的策略。然而，使用杂双功能PROTAC分子进行药物开发通常来讲受限于差的膜通透性、低活体效率和不加区分的分布。

课题组开发了一种适体-PROTAC接合的方法，作为一种新型概念，优化肿瘤特异性靶向能力和普通PROTACs的活体抗肿瘤潜力。作为概念证明，第一个适体-PROTAC缀合物通过以可清除链体连接一个BET靶向PROTAC到核酸适体AS1411（AS）。与未改性BET PROTAC相比，设计的分子（APR）显示出在MCF-7异种移植模型中优化的肿瘤靶向能力，导致增强的活体BET降解、抗肿瘤潜力和减弱的毒性。因此，APC策略可能为肿瘤特异性靶向PROTACs的设计铺平道路，且在开发基于PROTAC的药物上有广泛应用。

附：英文原文

Title: Aptamer-PROTAC Conjugates (APCs) for Tumor-specific Targeting in Breast Cancer

Author: Shipeng He, Fei Gao, Junhui Ma, Haoqian Ma, Guoqiang Dong, Chunquan Sheng

Issue&Volume: 2021-07-09

Abstract: Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed as a novel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs.

DOI: 10.1002/anie.202107347

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202107347