Aptamer‐PROTAC Conjugates (APCs) for Tumor‐Specific Targeting in Breast Cancer

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.

Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin

“…In this study, we further developed the first aptamer-constructed PROTAC ZL216 through combining ssDNA aptamer AS1411 with a small-molecule ligand of VHL, which demonstrate that in addition to peptides and small molecule compounds, the nucleic acid aptamers can also be used to construct PROTACs. Unlike the recently reported aptamer-conjugated BET-PROTAC using aptamer as targeted delivery tool for PROTAC in specific cell types,(22) ZL216 functioned as a novel PROTAC to promote the formation of nucleolin-ZL216-VHL ternary complex by using AS1411 as a ligand for binding to nucleolin, which potently induced the degradation of nucleolin in breast cancer cells in vitro and in vivo . Currently, few aptamers that specifically bind to E3 ligases are available; therefore, we only utilized the aptamer as a protein of interest (POI) ligand to construct PROTAC.…”

“…Recently, AS1411 was used as a targeted delivery tool to deliver BET-PROTAC into breast cancer cells for degrading BRD4 protein. (22) In this study, we report the first proof-of-concept evidence using nucleic acid aptamer to construct a novel PROTAC. Aptamer AS1411, as a targeting ligand for nucleolin, was conjugated to a small molecule ligand of E3 ligase VHL via a DBCO-azide click reaction, which generated a nucleolin-targeting PROTAC ZL216 with excellent serum stability and water solubility.…”

“…Recently, AS1411 was used as a targeted delivery tool to deliver BET-PROTAC into breast cancer cells for degrading BRD4 protein. (22)…”

Strategies for designing proteolysis targeting chimaeras (PROTACs)

“…252 Taking these advantages into account, our group developed an aptamer-PROTAC conjugation (APC) strategy to improve the tumor-targeting specificity of conventional PROTACs. 253 The first aptamer-PROTAC conjugate was designed by conjugating a BRD4-targeting PROTAC with nucleolin-targeting aptamer AS1411 through a glutathione (GSH)-sensitive linker (Figures 27 and 28…”

“…Aptamers exhibit significant advantages in targeted therapeutics due to facial chemical synthesis, good water solubility, and excellent tissue specificity and permeability 252 . Taking these advantages into account, our group developed an aptamer‐PROTAC conjugation (APC) strategy to improve the tumor‐targeting specificity of conventional PROTACs 253 . The first aptamer‐PROTAC conjugate was designed by conjugating a BRD4‐targeting PROTAC with nucleolin‐targeting aptamer AS1411 through a glutathione (GSH)‐sensitive linker (Figures 27 and 28).…”