Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents

Wang, Chao; Zhang, Yujing; Shi, Lingyu; Yang, Shanbo; Chang, Jing; Zhong, Yingjie; Li, Qian; Xing, Dongming

doi:10.1080/14756366.2022.2074414

Cited by 21 publications

(18 citation statements)

References 106 publications

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“…The SNIPER(AR) molecule with the AR ligand and IAP ligand produced effective protein knockdown activity against AR, suggesting that it could be a promising agent for prostate cancer (PC) [ 21 ]. In addition, 5 could effectively suppress AR-mediated gene expression and induce caspase activation and apoptosis in PC cells which did not emerge in cells treated with AR antagonists [ 22 ]. However, cIAP1-based PROTACs can also induce autoubiquitination and degradation of the E3 ligase itself [ 20 , 21 ], thus, limiting the full potential of the technology [ 23 ].…”

Section: Degraders Based On the Ubiquitin–proteasome Pathway (Upp)mentioning

confidence: 99%

Recent advances in targeted protein degraders as potential therapeutic agents

et al. 2023

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Section: Degraders Based On the Ubiquitin–proteasome Pathway (Upp)mentioning

confidence: 99%

Recent advances in targeted protein degraders as potential therapeutic agents

et al. 2023

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“…In addition to the use of VHL and CRBN, another family of E3 ligases known as IAPs has also been harnessed in the development of PROTACs [ 30 , 31 , 32 ]. Our research team synthesized a series of VHL-, CRBN-, and IAP-based PROTACs targeting estrogen receptor alpha (ERα) ( Figure 2 ), a TF able to form transcriptional complexes on the promoter region to initiate gene expression [ 33 ].…”

Section: Proatc-based Protein Degraders Warheaded With Single-strande...mentioning

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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“…284 Specifically, the pink moiety is exposed to the solvent as a potentially ideal linking position in the design of PROTAC degraders, based on the crystal structure of IAPs inhibitor with IAPs protein (Figure 5; PDB ID: 5M6H). 369,370 F I G U R E 4 A variety of small molecules that serve as the ligands for MDM2 E3 ligase. (A-D) Various small molecules (MDM2-1-4) acting as MDM2 E3 ligase ligands and proposed tethering position in MDM2 ligand, based upon a co-crystal structure of the MDM2 inhibitor nutlin-3 and MDM2 protein (PDB ID: 4J3E).…”

Section: 1mentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents

Cited by 21 publications

References 106 publications

Recent advances in targeted protein degraders as potential therapeutic agents

Recent advances in targeted protein degraders as potential therapeutic agents

Current Status of Oligonucleotide-Based Protein Degraders

PROTACs: A novel strategy for cancer drug discovery and development

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