Developing potent LC3-targeting AUTAC tools for protein degradation with selective autophagy

Pei, Junping; Pan, Xiaoli; Wang, Aoxue; Wen, Shuai; Bu, Faqian; Tang, Pan; Shuai, Zhang; Zhang, Yiwen; Wang, Guan; Ouyang, Liang

doi:10.1039/d1cc04661f

Cited by 36 publications

(50 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, ATTECs are capable of degrading the nuclear protein BRD4. 144 It is important to note that the nuclear autophagy may not involve SQSTM1/p62, and thus the SQSTM1/p62-engaging degrader including AUTACs or AUTO-TACs may have limited effects on nuclear protein, consistent with the observation that AUTAC3, the BRD4-targeting AUTAC, has little effect on the nuclear protein BRD4. 7 The other potential mechanism that may allow ATTECs to degrade nuclear proteins is the balance between cytoplasmic and nuclear distribution of the POI.…”

Section: Subcellular Localizationsupporting

confidence: 62%

“…95,136,142,143 To test whether BRD4 can also be effectively degraded by ATTECs using the LC3-binding warheads, Pei et al successfully synthesized chimeric compounds by linking the LC3-binding warhead GW5074 from its phenoxyl group to JQ1 with a suitable linker. 144 Their data demonstrate that some of these compounds can degrade the BRD4 protein likely through the autophagy pathway. Noticeably, they did a pilot study on the linkerology of the chimeric ATTECs and suggested that the linker length and composition strongly influence the degradation efficacy and potency.…”

Section: Attecsmentioning

confidence: 98%

“…9 In contrast, the effects of LDÁATTECs and BRD4ÁATTECs were significantly enhanced by the treatment with the autophagy enhancer rapamycin. 10,144,223 The exact mechanistic explanation is unclear, but LDs and BRD4 may require a more significant number of autophagosomes for degradation because of LDs' high level in the OA-induced cells and BRD4's limited accessibility to autophagosomes due to its nuclear localization, respectively.…”

Section: Pathway-dependencementioning

confidence: 99%

See 2 more Smart Citations

Emerging degrader technologies engaging lysosomal pathways

et al. 2022

View full text Add to dashboard Cite

show abstract

Section: Subcellular Localizationsupporting

confidence: 62%

Section: Attecsmentioning

confidence: 98%

Section: Pathway-dependencementioning

confidence: 99%

See 1 more Smart Citation

Emerging degrader technologies engaging lysosomal pathways

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Autophagy, and specifically the LC3/GABARAP family of proteins, is also an emerging avenue for targeted protein degradation . Autophagy-targeting chimeras (called AUTACs, among other acronyms) − link a compound that binds a protein-of-interest to another compound that promotes recruitment to the autophagosome. AUTACs could have several advantages over proteolysis-targeting chimeras (PROTACs) because autophagy components such as LC3/GABARAP are broadly expressed in all tissue types and because autophagosome recruitment requires only physical tethering, not catalysis within a ternary complex.…”

Section: Discussionmentioning

confidence: 99%

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

et al. 2022

View full text Add to dashboard Cite

The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized ovarian cancer cells to cisplatin. These small, potent stapled peptides represent promising autophagy-modulating compounds that can be developed as novel cancer therapeutics and novel mediators of targeted protein degradation.

show abstract

“…AUTACs (Autophagy-targeting chimeras) are small molecule degraders that high-jack the autophagy machinery to degrade proteins and even whole organelles [ 131–133 ]. The first class of these degraders are based on the ubiquitin-dependent autophagic clearance of group A Streptococcus (GAS).…”

Section: Autacs: Bypassing Mitophagy Machinery With Small Moleculesmentioning

confidence: 99%

Therapeutic targeting of mitophagy in Parkinson's disease

Masaldan

Callegari

Dewson

2022

Biochemical Society Transactions

View full text Add to dashboard Cite

Parkinson's disease is a neurodegenerative disorder characterised by cardinal motor symptoms and a diverse range of non-motor disorders in patients. Parkinson's disease is the fastest growing neurodegenerative condition and was described for the first time over 200 years ago, yet there are still no reliable diagnostic markers and there are only treatments that temporarily alleviate symptoms in patients. Early-onset Parkinson's disease is often linked to defects in specific genes, including PINK1 and Parkin, that encode proteins involved in mitophagy, the process of selective autophagic elimination of damaged mitochondria. Impaired mitophagy has been associated with sporadic Parkinson's and agents that damage mitochondria are known to induce Parkinson's-like motor symptoms in humans and animal models. Thus, modulating mitophagy pathways may be an avenue to treat a subset of early-onset Parkinson's disease that may additionally provide therapeutic opportunities in sporadic disease. The PINK1/Parkin mitophagy pathway, as well as alternative mitophagy pathways controlled by BNIP3L/Nix and FUNDC1, are emerging targets to enhance mitophagy to treat Parkinson's disease. In this review, we report the current state of the art of mitophagy-targeted therapeutics and discuss the approaches being used to overcome existing limitations to develop innovative new therapies for Parkinson's disease. Key approaches include the use of engineered mouse models that harbour pathogenic mutations, which will aid in the preclinical development of agents that can modulate mitophagy. Furthermore, the recent development of chimeric molecules (AUTACs) that can bypass mitophagy pathways to eliminate damaged mitochondria thorough selective autophagy offer new opportunities.

show abstract

Developing potent LC3-targeting AUTAC tools for protein degradation with selective autophagy

Abstract: Autophagy-based protein degradation is emerging as a promising technology for anti-diseases and innovative drug discovery.

Cited by 36 publications

References 24 publications

Emerging degrader technologies engaging lysosomal pathways

Emerging degrader technologies engaging lysosomal pathways

Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

Therapeutic targeting of mitophagy in Parkinson's disease

Contact Info

Product

Resources

About