Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera)

Ji, Chang Hoon; Lee, Min Ju; Kim, Hee Yeon; Heo, Ah Jung; Park, Daniel Youngjae; Kim, Yun Kyung; Kim, Bo Yeon; Kwon, Yong Tae

doi:10.1080/15548627.2022.2091338

Cited by 12 publications

(9 citation statements)

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“…The more recently developed AUTOTAC platform coopts autophagy for target protein degradation in a ubiquitinindependent manner. [41] AUTOTAC is a chemical dimerizer built upon a target protein binder and a ligand for an autophagosome targeting receptor (e. g. p62). Interestingly, AUTOTACs induced the degradation of a broad range of soluble target proteins (ERβ, AR, and MetAP2) and misfolded tau aggregates via the autophagy-lysosome pathway.…”

Section: Co-opting the Macro-autophagy Pathway (Autacs Attecs Autotacs)mentioning

confidence: 99%

TAC‐tics for Leveraging Proximity Biology in Drug Discovery

Nalawansha,

Mangano,

den Besten

et al. 2024

ChemBioChem

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Chemically induced proximity (CIP) refers to co‐opting naturally occurring biological pathways using synthetic molecules to recruit neosubstrates that are not normally encountered or to enhance the affinity of naturally occurring interactions. Leveraging proximity biology through CIPs has become a rapidly evolving field and has garnered considerable interest in basic research and drug discovery. PROteolysis Targeting Chimera (PROTAC) is a well‐established CIP modality that induces the proximity between a target protein and an E3 ubiquitin ligase, causing target protein degradation via the ubiquitin‐proteasome system. Inspired by PROTACs, several other induced proximity modalities have emerged to modulate both proteins and RNA over recent years. In this review, we summarize the critical advances and opportunities in the field, focusing on protein degraders, RNA degraders and non‐degrader modalities such as post‐translational modification (PTM) and protein‐protein interaction (PPI) modulators. We envision that these emerging proximity‐based drug modalities will be valuable resources for both biological research and therapeutic discovery in the future.

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Section: Co-opting the Macro-autophagy Pathway (Autacs Attecs Autotacs)mentioning

confidence: 99%

TAC‐tics for Leveraging Proximity Biology in Drug Discovery

Nalawansha,

Mangano,

den Besten

et al. 2024

ChemBioChem

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“…2(B)). 81,82 In the N-degron pathway, formerly known as the ''N-end rule'' pathway, the in vivo half-life of a protein is primarily determined by its N-terminal amino acid. 83,84 In the initial N-end rule, each amino acid within the genetic code was categorised into either ''stabilizing'' (including the start codon Met) or ''destabilizing'' (including positively charged Arg) residues for proteasomal degradation; however, it is now understood that all 20 amino acids can serve as N-degrons.…”

Section: Autophagy-targeting Chimera (Autotac)mentioning

confidence: 99%

Targeted protein degradation directly engaging lysosomes or proteasomes

Kim,

Byun,

Kim

et al. 2024

Chem. Soc. Rev.

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“…This AUTOTAC had been demonstrated to decrease the level of AR protein successfully at 0.5–10 µM concentrations in LNCaP cells [ 55 ]. Unlike the UPS which degrades small unfolded and misfolded proteins, the autophagy–lysosome system digests a broader range of large substrates, including insoluble mutant protein, degenerated mitochondria, and peroxisomes [ 56 ]. Although the idea of AUTOTAC was newly proposed and its application is currently limited, it is still promising for AUTOTAC to synergize with PROTAC in the depletion of AR protein in the near future.…”

Section: Alternative Ar-targeted Therapeutic Choicesmentioning

confidence: 99%

The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer

Xu²

2022

Clin Transl Oncol

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Androgen receptor (AR) plays a vital role in prostate cancer (PCa), including castration-resistant PCa, by retaining AR signalling. Androgen deprivation treatment (ADT) has been the standard treatment in the past decades. A great number of AR antagonists initially had been found effective in tumour remission; however, most PCa relapsed that caused by pre-translational resistance such as AR mutations to turn antagonist into agonist, and AR variants to bypass the androgen binding. Recently, several alternative therapeutic choices have been proposed. Among them, proteolysis targeting chimera (PROTAC) acts different from traditional drugs that usually function as inhibitors or antagonists, and it degrades oncogenic protein and does not disrupt the transcription of an oncogene. This review first discussed some essential mechanisms of ADT resistance, and then introduced the application of AR-targeted PROTAC in PCa cells, as well as other AR-targeted therapeutic choices.

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Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera)

Cited by 12 publications

References 1 publication

TAC‐tics for Leveraging Proximity Biology in Drug Discovery

TAC‐tics for Leveraging Proximity Biology in Drug Discovery

Targeted protein degradation directly engaging lysosomes or proteasomes

The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer

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