Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)

Zhang, Zhimin; Chang, Xinyue; Zhang, Chixiao; Zeng, Shenxin; Liang, Meihao; Ma, Zhen; Wang, Zunyuan; Huang, Wenhai; Shen, Zhengrong

doi:10.1080/14756366.2020.1804382

Cited by 31 publications

(19 citation statements)

References 38 publications

(44 reference statements)

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“…In 2020, Shen group developed several PARP1 degraders based on the combination of PARP1 inhibitor Olaparib and lenalidomide. 395 The representative degrader 207 (Fig. 61 ) effectively induced the degradation of PARP1 at 10 µM in SW620 cells.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 95%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

115

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 95%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

115

View full text Add to dashboard Cite

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“…In 2019, by connecting niraparib and the MDM2 ligand nutlin-3, Zhao et al synthesized the PARP1-targeting PROTAC compound 3 to induce significant apoptosis of TNBC cells without cytotoxicity against normal cells [ 191 ]. Olaparib was also used to design CRBN-recruiting PROTACs to trigger apoptosis in multiple cancers [ 169 , 188 ]. To improve selectivity, Wang et al utilized rucaparib (a selective PARP1 inhibitor) and CRBN ligand to develop PARP1 degrader iRucaparib-AP5, which exerted highly specific PARP1 degradation in cervical, breast, renal and prostate cancer cells [ 170 ].…”

Section: Protacs In Targeted Cancer Therapymentioning

confidence: 99%

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Zheng

et al. 2022

Mol Cancer

127

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Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs.

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“…PROTACs using olaparib, rucaparib, and niraparib derivatives were developed and tested in cancer and non-cancer cells ( Table 2 ). They showed superior cytotoxicity compared to that of conventional inhibitors and a wider range of uses beyond BRCA mutant cancers [ 77 , 78 , 79 ]. Among them, PROTAC using niraparib and MDM2 ligand exhibited PARP1 degradation and also increased PARP cleavage in MDA-MB-231 breast cancer cells.…”

Section: Lessons From Bench: How Can We Overcome Resistance To Parpi ...mentioning

confidence: 99%

PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

Kim

Nam

2022

IJMS

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PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.

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Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)

Cited by 31 publications

References 38 publications

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

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