Targeted protein degradation: mechanisms, strategies and application

Zhao, Lin; Zhao, Jia; Zhong, Kunhong; Tong, Aiping; Jia, Da

doi:10.1038/s41392-022-00966-4

Cited by 264 publications

(212 citation statements)

References 148 publications

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“…To examine the requirement of TRIM24 for induction of HIV-1 we used a Von Hippel-Lindau (VHL)-engaging functional degrader of TRIM24, designated dTRIM24 [27]. This chemical derivative is comprised of IACS-9571 conjugated to the VHL binding ligand VL-269 to produce proteolysis-targeting chimeric compound (PROTAC), which promote degradation of target proteins by forcing interaction with the VHL ubiquitin ligase [28]. Treatment of cells with dTRIM24 conjugate causes degradation of TRIM24 in Jurkat cells at concentrations between 0.5-5 mM after 24 hours, as determined by immunoblotting (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Horvath

Brumme

Sadowski

2022

Preprint

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Expression of the HIV-1 genome by RNA Polymerase II is regulated at multiple steps, as are most cellular genes, including recruitment of general transcription factors and control of transcriptional elongation from the core promoter. We recently discovered that tripartite motif protein TRIM24 is recruited to the HIV-1 Long Terminal Repeat (LTR) by interaction with TFII-I and causes transcriptional elongation by stimulating association of PTEF-b/ CDK9. Because TRIM24 is required for stimulation of transcription from the HIV-1 LTR, we were surprised to find that IACS-9571, a specific inhibitor of the TRIM24 C-terminal bromodomain, induces HIV-1 provirus expression in otherwise untreated cells. IACS-9571 reactivates HIV-1 in T cell lines bearing multiple different provirus models of HIV-1 latency. Additionally, treatment with this TRIM24 bromodomain inhibitor encourages productive HIV-1 expression in newly infected cells and inhibits formation of immediate latent transcriptionally repressed provirus. IACS-9571 synergizes with PMA, ionomycin, TNF-α and PEP005 to activate HIV-1 expression. Furthermore, co-treatment of CD4 + T cells from individuals with HIV-1 on antiretroviral therapy (ART) with PEP005 and IACS-9571 caused robust provirus expression. Notably, IACS-9571 did not cause global activation of T cells; rather, it inhibited induction of IL2 and CD69 expression in human PBMCs and Jurkat T cells treated with PEP005 or PMA. These observations indicate the TRIM24 bromodomain inhibitor IACS-9571 represents a novel HIV-1 latency reversing agent (LRA), and unlike other compounds with this activity, causes partial suppression of T cell activation while inducing expression of latent provirus.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Horvath

Brumme

Sadowski

2022

Preprint

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“…Mechanistically, FTO exerts its activity through the regulation of m 6 A levels of target genes including SLC1A5, BRD9, and PGC-1α in ccRCC. Significant progress has been made in the development of FTO inhibitors, however, novel strategies such as molecular degrader-induced targeted protein degradation [80] have not been tested in therapeutic inhibition of FTO. Further investigations are needed to better understand the role of FTO in RCC to help determine the potential of developing FTO inhibitors as novel therapeutic agents to treat RCC.…”

Section: Discussionmentioning

confidence: 99%

The controversial role and therapeutic development of the m6A demethylase FTO in renal cell carcinoma

Zhang

Wornow

Peehl

et al. 2022

Translational Oncology

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“…Recently, targeted protein degradation strategies via the lysosomal pathway have been explored that as well could degrade membrane proteins, extracellular proteins, and protein aggregates, thus greatly expanding the range of substrates for TPD. 147 As a result of intensive research in the area, a number of new strategies via the lysosomal pathway, such as LYTAC, AbTAC, ATTEC, AUTAC, bispecific aptamer chimeras, and AUTOTAC have recently emerged. 148 In the long run, structure-based rational optimization approaches for perfection of the targeted protein degraders are highly needed.…”

Section: Discussionmentioning

confidence: 99%

Molecular glues: The adhesive connecting targeted protein degradation to the clinic

Sasso

Tenchov

Wang

et al. 2022

Preprint

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Targeted protein degradation is a rapidly exploding drug discovery strategy which uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer, infectious, inflammatory, and neurodegenerative diseases, especially for those with “undruggable” pathogenic protein targets. With the recent rise of the ‘molecular glue’ type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.

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Targeted protein degradation: mechanisms, strategies and application

Cited by 264 publications

References 148 publications

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

The controversial role and therapeutic development of the m6A demethylase FTO in renal cell carcinoma

Molecular glues: The adhesive connecting targeted protein degradation to the clinic

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