Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.

2025-12-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met amplification-mediated PARP1i acquired-resistance

Article

作者: Wang, Runyuan ; Hu, Mengxuan ; Zhai, Bingxin ; Sun, Zeren ; Xu, Jie ; Zhang, Yuchen ; Zou, Yi ; Zhu, Qihua ; Wang, Boning ; Xu, Yungen ; Hu, Zheqi ; Zhang, Wenbin

PARP1 is a well-established therapeutic target in cancer treatment, based on the principle of synthetic lethality. However, the development of drug resistance has significantly compromised the antitumor efficacy of PARP1 inhibitors, exemplified by resistance mediated through c-Met amplification. In this study, we report the development of a novel PARP1/c-Met dual inhibitor derived from the benzofuran-7-carboxamide moiety of the PARP1 inhibitor Mefuparib. Compared with compound 16 obtained in the previous study, compound S12 was identified as a highly potent dual inhibitor with lower molecule weight and better solubility, demonstrating robust inhibitory activity against both PARP1 (IC₅₀ = 21.8 nM) and c-Met (IC₅₀ = 30.2 nM). Importantly, S12 exhibited remarkable anti-tumor efficacy in the HCT116OR xenograft models, suggesting that targeting both PARP1 and c-Met represents an effective therapeutic strategy to overcome PARP1 inhibitor resistance mediated by c-Met amplification.

2025-10-01·Recent Patents on Anti-Cancer Drug Discovery

Patents on PARP-1 Inhibitors for the Management of Cancer from 2017-2023

Article

作者: Singh, Ankit Kumar ; Kumar, Adarsh ; Singh, Harshwardhan ; Kumar, Pradeep

Background::

There are eighteen members of the Poly (ADP-ribose) polymerases (PARPs) family, which oversee various cellular processes such as maintaining the integrity of the genome, regulating transcription, cell cycle progression, initiating the DNA damage response, and apoptosis. PARP1 is an essential member of the PARP family and plays a crucial role in repairing single-strand breaks in eukaryotic cells through a process called BER (base excision repair). It is the most extensively studied and commonly found member of this family.

Area Covered::

This article discusses the advancements in developing PARP inhibitors for human cancers. It covers the discovery of new PARP1 inhibitors with chemical classification that selectively target multiple areas using cancer models in vitro and in vivo and evaluates them critically. The focus is on patents that have been published from 2017 to 2023, except tankyrase inhibitors.

Expert Opinion::

PARP1 inhibitors were developed by various companies and academic groups from the 1990s to enhance the effectiveness of chemo and radiotherapy. However, their progress was hindered due to their severe toxicity when combined with these treatments. Therefore, on finding PARP1 inhibitors that can amplify the ability of chemotherapy agents to kill tumors while causing minimal toxicity, these substances can either be used alone as part of the synthetic lethality approach or in conjunction with radiotherapy or chemotherapy, resulting in a mutually beneficial outcome.

100 项与 PARP1 inhibitors(Chengdu Zenitar Biomedical Technology) 相关的药物交易

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