A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer

Li, Ge; Lin, Shujing; Yu, Zelei; Wu, Xinhua; Liu, Jingwen; Tu, Guihui; Liu, Quanyu; Tang, Yuan-ling; Jiang, Qingna; Xu, Jiang; Huang, Qingling; Wu, Lixian

doi:10.1016/j.bcp.2022.115329

Cited by 32 publications

(20 citation statements)

References 53 publications

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“…The absence of ubiquitinated labeled proteins at 24 h could be due to the rapid degradation of ubiquitinated proteins in the proteasome, as previously reported. 45 , 46 Therefore, MG132 was used to observe the ubiquitin proteins. In the presence of MG132, the content of ubiquitin proteins induced by PRO‐6 E increased significantly, supporting a proteasome‐dependent manner (Figure 4P ).…”

Section: Resultsmentioning

confidence: 99%

Crizotinib‐based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

Chen

Jin

et al. 2023

Cancer Science

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As one of the common malignant cancer types, gastric cancer (GC) is known for late‐stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the “occupancy‐driven” model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET‐targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO‐6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET‐positive GC cells. In the MKN‐45 xenograft model, PRO‐6 E showed pronounced antitumor efficacy with a well‐tolerated dosage regimen. These results validated PRO‐6 E as the first oral PROTAC for MET‐dependent GC.

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Section: Resultsmentioning

confidence: 99%

Crizotinib‐based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

Chen

Jin

et al. 2023

Cancer Science

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“…Furthermore, PARP1 was degraded using PROTACs by Li et al (2022). First, Pu et al developed the PROTAC LB23 by linking a CRBN ligand to Olaparib (Figure 5a) .…”

Section: Protacs Targeting Parpsmentioning

confidence: 99%

“…Second, In the Li et al study, the PROTAC NN3, consisting of Niraparib tethered into Nutlin-3a, an MDM2 ligand, was used to degrade PARP1 in MDA-MB-231 and MCF-7 (Li et al, 2022). NN3 showed potent antiproliferative activity and low toxicity in TNBC cells in vitro and in vivo, with a unique mechanism involving ferroptosis promotion through the downregulation of the SLC7A11 pathway downregulation in p53+ cells (Li et al, 2022).…”

Section: Protacs Targeting Parpsmentioning

confidence: 99%

“…In addition, LB23 demonstrated negligible degradation toxicity in normal cells and a 60‐fold selectivity for degradation in tumor cells, and the DC50 value for PARP1 degradation in LB23 to L‐02 cells was 3.2 µM (Pu, Wang, et al, 2022). Second, In the Li et al study, the PROTAC NN3, consisting of Niraparib tethered into Nutlin‐3a, an MDM2 ligand, was used to degrade PARP1 in MDA‐MB‐231 and MCF‐7 (Li et al, 2022). NN3 showed potent antiproliferative activity and low toxicity in TNBC cells in vitro and in vivo, with a unique mechanism involving ferroptosis promotion through the downregulation of the SLC7A11 pathway downregulation in p53+ cells (Li et al, 2022).…”

Section: Protac As a Promising Therapeutic Agent In Tnbcmentioning

confidence: 99%

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Proteolysis Targeting Chimera (PROTAC) as a promising novel therapeutic modality for the treatment of triple‐negative breast cancer (TNBC)

Dogheim

Amralla²

2023

Drug Development Research

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Breast cancer (BC) is considered one of the most prevalent malignancies impacting women worldwide, constituting 15% of all new cancer cases. It is classified according to its molecular targets into three subtypes; HR+/ERBB2‐, ERBB2+/HR+, or HR‐ and triple‐negative breast cancer (TNBC). TNBC is considered aggressive cancer with bad prognosis and poor clinical outcomes. It lacks estrogen, progesterone, and ERBB2 receptors rendering its treatment more challenging. Owing to its unresponsiveness to hormonal therapy, quick tumor growth, and the high probability to have spread at the time of discovery, it is more likely to recur following therapy. Proteolysis Targeting Chimeric molecules (PROTACs) are hetero‐bifunctional molecules that are able to hijack the ubiquitin‐proteasome system, a major physiological proteolytic mechanism. This leads to ubiquitination through endogenous E3 ligases and subsequent degradation through 26‐S proteasome. Since its discovery in 2001, PROTACs have been considered an important therapeutic modality due to their ability to target and degrade undruggable proteins. In vitro studies have been conducted to investigate the possibility of using PROTACs as a therapeutic modality in TNBC. Data available propose great potential of PROTACs technology as a major candidate in TNBC management. Further in vitro and in vivo clinical trials are required to establish a definitive decision. In this review, we aim to give a brief overview of TNBC and PROTACs and highlight the rationale behind using PROTACs as a therapeutic modality in patients with TNBC.

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“…Since then, a series of novel and highly effective VHL E3 ligase ligands have been discovered and reported, typified by compounds VHL‐1–VHL‐8 (Figure 2) with improved lipophilicity 119,120,122 . The studies on the eutectic structure of the VHL ligand with the protein helps to locate the solvent‐exposed region, leading to revelation of four possible linking sites without negatively affecting the interaction between the protein and the corresponding ligand (Figure 2; PDB ID: 4W9H) 123–134 . These sites are (a) terminal amino; (b) sulfhydryl; (c) benzyl; and (d) phenolic hydroxyl group on the benzene ring 113,135–141 .…”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

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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A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer

Cited by 32 publications

References 53 publications

Crizotinib‐based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

Crizotinib‐based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

Proteolysis Targeting Chimera (PROTAC) as a promising novel therapeutic modality for the treatment of triple‐negative breast cancer (TNBC)

PROTACs: A novel strategy for cancer drug discovery and development

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