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

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

doi:10.1016/j.omtn.2022.09.008

Cited by 47 publications

(33 citation statements)

References 40 publications

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“…The use of a VHL binder, (S, R, S)-AHPC-PEG3-azide, as a competitor against ZL216 significantly rescued the effect of ZL216-induced nucleolin degradation in MCF7 and BT474 cells. Additionally, ZL216 inhibited the proliferation and migration of breast cancer cells in vitro [ 22 ]. This study further validates the selectivity of AS1411 for cancer cells over normal cells, and aptamers can be harnessed as POI recruiters in addition to small molecule binders.…”

Section: Aptamer-protac Conjugates and Aptamer-warheaded Protacmentioning

confidence: 99%

Current Status of Oligonucleotide-Based Protein Degraders

et al. 2023

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Transcription factors (TFs) and RNA-binding proteins (RBPs) have long been considered undruggable, mainly because they lack ligand-binding sites and are equipped with flat and narrow protein surfaces. Protein-specific oligonucleotides have been harnessed to target these proteins with some satisfactory preclinical results. The emerging proteolysis-targeting chimera (PROTAC) technology is no exception, utilizing protein-specific oligonucleotides as warheads to target TFs and RBPs. In addition, proteolysis by proteases is another type of protein degradation. In this review article, we discuss the current status of oligonucleotide-based protein degraders that are dependent either on the ubiquitin–proteasome system or a protease, providing a reference for the future development of degraders.

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Section: Aptamer-protac Conjugates and Aptamer-warheaded Protacmentioning

confidence: 99%

Current Status of Oligonucleotide-Based Protein Degraders

et al. 2023

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“…Aptamer-PROTAC conjugates were especially expected to be more advantageous over antibody-PROTAC conjugates since they have higher physiological stability and can circumvent the antibody-attributed immunogenicity [ 110 , 111 ]. L. Zhang et al developed an aptamer-based PROTAC using nucleolin-binding aptamer and VHL E3 ligase recruiter, whose concept was slightly different from that of aptamer-PROTAC conjugates [ 112 ]. Aptamers were directly connected to E3 ligase recruiters without any additional POI warheads or stimuli-sensitive bonds, so the aptamer performed as both active targeting moieties and POI ligands.…”

Section: Cancer-specific Protac Delivery Systemmentioning

confidence: 99%

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

et al. 2023

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Proteolysis-targeting chimeras (PROTACs) are rapidly emerging as a potential therapeutic strategy for cancer therapy by inducing the degradation of tumor-overexpressing oncogenic proteins. They can specifically catalyze the degradation of target oncogenic proteins by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway. Since their mode of action is universal, irreversible, recyclable, long-lasting, and applicable to ‘undruggable’ proteins, PROTACs are gradually replacing the role of conventional small molecular inhibitors. Moreover, their application areas are being expanded to cancer immunotherapy as various types of oncogenic proteins that are involved in immunosuppressive tumor microenvironments. However, poor water solubility and low cell permeability considerably restrict the pharmacokinetic (PK) property, which necessitates the use of appropriate delivery systems for cancer immunotherapy. In this review, the general characteristics, developmental status, and PK of PROTACs are first briefly covered. Next, recent studies on the application of various types of passive or active targeting delivery systems for PROTACs are introduced, and their effects on the PK and tumor-targeting ability of PROTACs are described. Finally, recent drug delivery systems of PROTACs for cancer immunotherapy are summarized. The adoption of an adequate delivery system for PROTAC is expected to accelerate the clinical translation of PROTACs, as well as improve its efficacy for cancer therapy.

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“…Recently, Tan and colleagues provided the first proof of concept evidence using nucleic acid aptamer as a targeting ligand [ 110 ]. The designed molecule ZL216 promoted the formation of nucleolin-ZL216-VHL ternary complex by using AS1411 as a ligand for binding to nucleolin, which potently eliminated nucleolin in breast cancer cells in vitro and in vivo, and inhibited proliferation and migration of breast cancer cells in vitro [ 110 ]. Although ZL216 confers enhanced water solubility and tumor-selective binding, the therapeutic potential and pharmacokinetic features in vivo require further evaluation.…”

Section: Targeted Protein Degradation Approachesmentioning

confidence: 99%

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

Salama¹,

Trkulja²,

Casanova³

et al. 2022

IJMS

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The field of targeted protein degradation (TPD) is a rapidly developing therapeutic modality with the promise to tame disease-relevant proteins in ways that are difficult or impossible to tackle with other strategies. While we move into the third decade of TPD, multiple degrader drugs have entered the stage of the clinic and many more are expected to follow. In this review, we provide an update on the most recent advances in the field of targeted degradation with insights into possible clinical implications for cancer prevention and treatment.

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

Cited by 47 publications

References 40 publications

Current Status of Oligonucleotide-Based Protein Degraders

Current Status of Oligonucleotide-Based Protein Degraders

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

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