Author: Li, Xiaodong ; Sun, Xing ; Wang, Xia ; Zhang, Hui ; Xie, Tiantian ; Peng, Tianhuan ; Li, Ling ; Ye, Mao ; Tan, Weihong ; Liu, Jing ; Zhang, Lin ; Zhang, Yibin ; Wu, Wencan ; Dai, Jing ; Liu, Huimin

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and are poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.

01 Dec 2022·Molecular Therapy - Nucleic Acids

An instructive attempt on developing aptamer-constructed PROTAC for breast cancer treatment

Author: Mi, Dazhao ; Chen, Yihua ; Zhang, Yuzhu

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional mols. that consist of a protein of interest (POI) ligand, an E3.Ubiquitin ligase (E3) ligand, and an optimized linker to attach both ligands.1 Upon binding to a POI, PROTACs induce proximity of the POI and E3.Result in the formation of a productive "POI-PROTACs-E3" ternary complex,which facilitates the ubiquitination and subsequent degradation of. The POI via the ubiquitin-proteasome system. In the past two decades, PROTACs have advanced.Dramatically and evolved from peptidebased PROTACs and small-mol.PROTACs to orally efficacious clin. candidates that degrade pathogenic proteins.In patients.2 In this issue of Mol. Therapy Nucleic Acids, Zhang et al. successfully developed a novel PROTAC that employed.Nucleic acid aptamer instead of a peptide or small mol. as the POI ligand.3 According to this design principle, they reported.The first nucleolin-targeting aptamer-constructed PROTAC ZL216, which selectively degraded nucleolin in vitro and in vivo.They also showed that ZL216 could inhibit the proliferation and migration of hormone.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	CN	Hunan University	01 Dec 2022

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