JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Lin Lingting,Chen Binyu,Yang Yourui,Deng Ruocheng,Niu Wenfei,Liu Jian,Xu Wei,Li Hua
Background Proteolysis-targeting chimeras (PROTACs) have emerged as a promising cancer therapeutic approach by targeting protein degradation to address undruggable targets and drug resistance associated with conventional therapies, yet their clinical translation is hindered by poor solubility and non-specific toxicity. Additionally, tumor heterogeneity and biological complexity frequently limit the efficacy of monotherapies, necessitating the development of multifunctional delivery systems. Results We engineered a dual microenvironment-responsive albumin to integrate conditional PROTAC activation with metabolic starvation and ferroptosis for synergistic antitumor efficacy within a unified therapeutic cascade. Ferrocene (Fc)-modified human serum albumin (HSA) via coupling chemistry was electrostatically complexed with glucose oxidase (GOD) and co-assembled with an azobenzene (AZO)-caged ARV-771 prodrug to yield HSA-Fc-GOD@ARV-771(AZO) nanoparticles that exhibited pH-triggered disassembly in acidic tumor environments. the released GOD consumes glucose and oxygen to generate hydrogen peroxide while inducing metabolic starvation and exacerbating hypoxia. The intensified hypoxia triggers nitroreductase to cleave the prodrug linker and release the active ARV-771, which subsequently degrades bromodomain containing protein 4. This degradation directly suppresses tumor cell proliferation and downregulates glutathione peroxidase 4 expression to sensitize cancer cells to oxidative damage. Concurrently, the ferrocene component converts the generated hydrogen peroxide into hydroxyl radicals via the Fenton reaction to amplify lipid peroxidation and ferroptotic cell death. The nanoplatform suppressed lung cancer cell viability to 10.8% in vitro and achieved 94.3% tumor growth inhibition in xenograft models without observable systemic toxicity. Conclusions This study demonstrates a precision therapeutic paradigm. It exploits tumor microenvironment characteristics to couple conditional drug activation with starvation and ferroptosis. This strategy offers a translatable framework for next generation’s cancer treatment. Graphical
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高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 12
·1-14
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IF 8.1
Chen Li,Zou Yahui,Sun Renhong,Huang Mei,Zhu Xiaotong,Tang Xiao,Yang Xiaobao,Li Dake,Fan Gaofeng,Wang Yu
Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Ge Li,Shan-shan Lin,Ze-lei Yu,Xin-hua Wu,Jing-wen Liu,Gui-hui Tu,Quan-yu Liu,Yuan-ling Tang,Qing-na Jiang,Jian-hua Xu,Qing-ling Huang,Li-xian Wu
Therapeutic targeting of the nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP1) with PARP inhibitors (PARPis) in patients with a homologous recombination (HR)- deficient phenotype based on the mechanism of synthetic lethality has been shown tremendous success in cancer therapy. With the clinical use of various PARPis, emerging evidence has shown that some PARPis offer hope for breakthroughs in triple-negative breast cancer (TNBC) therapy, regardless of HR status. However, similar to other conventional cytotoxic drugs , PARPis are also subject to the intractable problem of drug resistance. Notably, acquired resistance to PARPis caused by point mutations in the PARP1 protein is hard to overcome with current strategies. To explore modalities to overcome resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted chimaera (PROTAC) to degrade mutant PARP1 in TNBC. Here, we investigated a PARP1 PROTAC termed “ NN3 ″, which triggered ubiquitination and proteasome-mediated degradation of PARP1. Moreover, NN3 degraded PARP1 with resistance-related mutations. Interestingly, compared with other reported PARP1 degraders, NN3 exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. Furthermore, NN3 showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.
研究领域:
癌症生物学
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分子生物学
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药理学
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肿瘤学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Honglian Li,Zhihao Ni,Yuzhen Rao,Junzhe Zhang,Huiyi Guo,Haoxing Yuan,Hao Yang,Jiayun Chen,Chan Yang,Jigang Wang,Yu Rao,Shuwen Liu
Background and Purpose Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) that symbolizes a primary contributor of morbidity and mortality. Dihydroartemisinin (DHA; artenimol) shows good therapeutic effects on LN. Its pharmacological target remains unclear. Proteolysis targeting chimeras (PROTAC) technology was used to identify the targets of DHA in LN treatment. Experimental Approach The activity of a novel compound termed A1 was assessed through cytotoxicity and anti-inflammatory assays in vitro . The target of DHA was screened by the A1 integrating with proteomics and then validated via western blotting, co-immunoprecipitation (Co-IP), immunofluorescence, molecular docking, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) in vitro. Twenty-four-hour proteinuria, inflammatory cytokines, serum biochemical indicators, immune complex deposition and renal pathological injury were detected. Adeno-associated virus-mediated RNA interference in silencing CARD6 was conducted in vivo to comprehensively evaluate the effect and the target of DHA on MRL/lpr mice. Key Results CARD6 was the most notably degraded protein affected by A1 that identified as the target of DHA. Specifically, DHA interacted with CORE-CARD6 at the 481–949aa region. DHA blocked CARD6 to inhibit RIP2/NF-κB pathway, which manifested anti-inflammatory properties in vivo and in vitro . Silencing CARD6 ameliorated the inflammatory response of MRL/lpr mice. Notably, the inhibition effects of DHA on the MRL/lpr mice were abrogated when CARD6 was depleted. Conclusion and Implications CARD6 was a therapeutic target of DHA for LN management. This finding highlights the great potential of using PROTAC technology to effectively identify therapeutic targets of natural products. Graphical CARD6 was the most notably degraded protein affected by the novel compound PROTAC A1 that was identified as the target of dihydroartemisinin (artenimol; DHA) for lupus nephritis (LN) treatment. DHA demonstrated anti-inflammatory properties in vitro and renal protective effect in vivo by targeting CARD6/RIP2/NF-κB signalling pathway.
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高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
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2023
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IF 4.8
Jianchao Zhang,Caibing Ma,Yongjun Yu,Chaowei Liu,Lijing Fang,Hai Rao
Proteolysis-targeting chimera (PROTAC) that specifically targets harmful proteins for destruction by hijacking the ubiquitin-proteasome system (UPS) is emerging as a potent anti-cancer strategy. How to efficiently modulate the target degradation remains a challenging issue. In this study, we employ a single amino acid-based PROTAC, which uses the shortest degradation signal sequence as the ligand of the N-end rule E3 ubiquitin ligases to degrade the fusion protein BCR-ABL, an oncogenic kinase that drives the progression of chronic myeloid leukemia (CML). We find that the reduction level of BCR-ABL can be easily adjusted by substituting different amino acids. Furthermore, a single PEG linker is found to achieve the best proteolytic effect. Our efforts have resulted in effective degradation of BCR-ABL protein by the N-end rule pathway and efficient growth inhibition of K562 cells expressing BCR-ABL in vitro , and blunted tumor growth in a K562 xenograft tumor model in vivo . The PROTAC presented has unique advantages including lower effective concentration, smaller molecular size and modular degradation rate. Demonstrating the efficacy of the N-end rule-based PROTACs in vitro and in vivo , our study further expands the limited degradation pathways currently available for PROTACs in vivo and is easily adapted for broader applications in targeted protein degradation.
研究领域:
肿瘤学
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分子生物学
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药理学
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高影响因子
BIOORGANIC CHEMISTRY
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2024
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IF 4.5
Jiawen Yang,Yifan Wu,Qiaoliang Zhu,Xiaojuan Qu,Hongyue Ou,Haixia Liu,Yongqi Wei,Di Ge,Chunlai Lu,Biao Jiang,Xiaoling Song
The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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高影响因子
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