JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Jing Huang,Zhuo Yao,Bowen Li,Yuan Ping
Proteolysis-targeting chimera (PROTAC) is emerging as a new strategy to degrade target proteins in a precise way by taking advantage of the cellular ubiquitin-proteasome system. However, the potential cytotoxicity of PROTAC should be avoided to mitigate the off-target degradation of proteins in healthy tissues or cells. To address this issue, we herein present a strategy to cage a PROTAC with 4-(vinyloxy) benzyl carbonate ( MZ1-O ), which can be eliminated through a 3,6-dimethyl-1,2,4,5-tetrazine ( Tz )-mediated inverse electron-demand Diels-Alder (iEDDA) reaction to generate a BRD4 (bromodomain-containing protein 4) degrader, MZ1 . We further propose a dissolvable microneedle-assisted strategy for site-specific activation of MZ1-O that is delivered by a targeted delivery vector through systemic route in vivo , and demonstrate such a bioorthogonal strategy is efficient and precise for tumor treatment. Our study suggests that the bioorthogonal activation of PROTAC-based prodrug offers a highly specific and precise approach for cancer therapy.
研究领域:
药理学
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癌症研究
·
化学
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生物医学工程
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 7.088
Xing-Rong Wang,Shuai Wang,Hong-Xia Mu,Kai-Yan Xu,Xue-Ting Wang,Jian-Tao Shi,Qi-Hang Cui,Li-Wen Zhang,Shi-Wu Chen
VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro , as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC 50 : 0.084 ± 0.04 μM, D max : 73.7%) and HUVEC cells (DC 50 : 0.51 ± 0.10 μM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G 2 /M phase cycle arrest and apoptosis . All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2026
·
IF 7.3
Jiahui Liu,Ling Fang,Shijun Wen,Na Zhao,Yongshun Huang,Hongtao Liu,Baowei Chen,Tiangang Luan
Manipulating intracellular protein degradation systems provides extraordinary opportunities to find targeting proteins critical for drug discovery, as exemplified by proteolysis-targeting chimeras (PROTACs). Here, using trivalent arsenical-PROTAC (As(III)-PROTAC) probes, we developed an in situ proteolysis strategy to uncover the As-binding proteomes. Combined with proteomic analysis, this strategy identified 135 downregulated proteins in A549 human lung carcinoma cells, providing a candidate list for seeking As-binding proteins. Bioinformatics analysis revealed that they were involved in multiple pathways, such as the tricarboxylic acid cycle, DNA replication, and DNA repair. Karyopherin subunit α-2 (KPNA2) and cyclin-dependent kinase 1 (CDK1) could play core roles in the context of protein interactions. Western blotting confirmed the downregulation of embryonic ectoderm development (EED) and phospholipase A-2-activating (PLAA) proteins after the probe treatment. A cellular thermal shift assay (CETSA) exhibited intracellular binding of iAsIII to EED and PLAA. This work demonstrates the development and application of PROTAC probes for screening of As-binding proteomes and establishes a methodological foundation for comprehending the biological effects induced by arsenicals.
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Haoze Song,Jing Liang,Yuanyuan Guo,Yang Liu,Kuiru Sa,Guohong Yan,Wen Xu,Wei Xu,Lixia Chen,Hua Li
Glutathione peroxidase 4 (GPX4) is the most promising target for inducing ferroptosis . GPX4-targeting strategies primarily focus on inhibiting its activity or adjusting its cellular level. However, small inhibitors have limitations due to the covalent reactive alkyl chloride moiety, which could lead to poor selectivity and suboptimal pharmacokinetic properties. Herein, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) by connecting RSL3, a small molecule inhibitor of GPX4, with six different ubiquitin ligase ligands. As a highly effective degrader, compound 18a is a potent degrader (DC 50, 48h = 1.68 μM, D max, 48h = 85 %). It also showed an obvious anti-proliferative effect with the IC 50 value of 2.37 ± 0.17 μM in HT1080. Mechanism research showed that compound 18a formed a ternary complex with GPX4 and cIAP and induced the degradation of GPX4 through the ubiquitin-proteasome system pathway. Furthermore, compound 18a also induced the accumulation of lipid peroxides and mitochondrial depolarization, subsequently triggering ferroptosis. Our work demonstrated the practicality and efficiency of the PROTAC strategy and offered a promising avenue for designing degraders to induce ferroptosis in cancer cells.
研究领域:
肿瘤学
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药物化学
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细胞生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Xuechun Wang,Jie Yan,Yilei Zhao,Songyan Li,Zilin Ma,Xiuying Duan,Yuelan Wang,Jianwei Jiao,Changping Gu,Guiqiang Zhang
Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy to selectively degrade target proteins in the treatment of various diseases. However, it has low bioavailability due to strong hydrophobicity, poor membrane permeability, and nonspecific distribution in vivo, which greatly limits its application. In this study, self-delivery PROTAC nanoparticles (designated as CP NPs) integrating gefitinib-based PROTACs and photosensitizers were developed to efficiently degrade mutated epidermal growth factor receptor (EGFR), a crucial kinase for cell growth and survival, while simultaneously triggering photodynamic therapy and immunotherapy. The prepared NPs enhanced the tumor accumulation of PROTACs, which led to the selective degradation of EGFR mutations and a reduction in programmed cell death protein ligand 1 levels, thereby alleviating tumor immunosuppression and immune tolerance. Moreover, under laser irradiation, the coloaded photosensitizers triggered potent photodynamic therapy effects and induced immunogenic cell death, which worked synergistically with PROTACs toward eliciting a robust antitumor immune response. In a mouse model of lung cancer, primary, distant, and lung metastatic tumors were significantly suppressed. This work highlights the potential of nano-PROTACs for degrading target proteins and facilitating combination photodynamic immunotherapy toward expanding PROTAC applications in cancer therapy.
研究领域:
肿瘤学
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药理学
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免疫学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Lidong Gong,Ridong Li,Jingjing Gong,Xianling Ning,Jiawei Sun,Qiang Ma,Chuanda Zhu,Yuanyuan Yang,Kerui Lin,Yanglonghao Li,Qiang Zhang,Tiancheng Li,Zhiqiang Lin
The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1 . At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.
研究领域:
癌症研究
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药物化学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2026
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IF 6.2
Xue Dong,Lin Wang,Sijia Lin,Ziyi Wang,Xueyong Qi,Jin Cao,Jing Zhang,Lin Wu,Song Shen
Hyperuricemia, characterized by an elevated serum uric acid level due to the abnormal xanthine oxidase (XOD)-mediated uric acid production, is generally associated with multiple systemic disorders. In this study, XOD-targeting proteolysis-targeting chimera (PROTAC) is developed to degrade the XOD and investigate the subsequent cellular behaviors. Febuxostat, a selective inhibitor of XOD, is used as a target molecule to bind the ligand of CRBN E3 ligase via a polyethylene glycol linker.The synthesized chimera, DeXOD, combined with XOD, mediates the ubiquitination and degradation of target proteins in hepatocellular carcinoma cells (HepG2) via the proteasome pathway. In the hyperuricemia mouse, the DeXOD significantly reduces XOD and serum uric acid levels, and also alleviates the uric acid-induced inflammation and oxidative stress. The expression of renal inflammatory factors IL-1β, IL-18, and TNF-α is remarkably attenuated, accompanied by the elevation of superoxide dismutase (SOD) and glutathione (GSH) levels and the decrease of malondialdehyde (MDA). Furthermore, the DeXOD can ameliorate glomerular capsular dilatation and renal tubular epithelial damage, while demonstrating no observable hepatotoxic effects. This strategy effectively circumvents the therapeutic limitations of conventional xanthine oxidase inhibitors, thereby offering a promising therapeutic paradigm for hyperuricemia and its complications.
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Junyao Li,Huan Min,Yan Song,Rong Huo,Lin Du,Yongzheng Li,Yajing Du,Wei Ding,Yinlong Zhang,Yiye Li,Guangjun Nie,Yingqiu Qi
Abstract Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF3-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF3-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF3-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF3-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF3-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF3-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF3-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF3-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.
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高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 39
·期 3
·e6090
·
IF 1.7
Fang Wang,Wenfei Sun,Zheheng Ma,Furui Chu
Proteolysis targeting chimera (PROTAC) has been developed and currently enjoys widespread interest among the field of pharmaceutical manufacturing in recent decades. NX-5948 is an orally active PROTAC Bruton tyrosine kinase degrader, which shows anti-inflammatory and antitumor activities. In this study, a simple and fast bioanalytical method for the quantification of NX-5948 in beagle dog plasma was developed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). A full method validation was performed according to regulatory guidelines. For the quantification, [M + H] + was formed using an electrospray ionization (ESI) source in the positive ion mode, and selective reaction monitoring (SRM) was employed using a triple quadrupole mass spectrometry. The monitored precursor-to-product transitions were m/z 807.5 > 790.5 for NX-5948 and m/z 812.4 > 452.1 for internal standard. A linear response was obtained at the concentration range of 0.5–200 ng/mL, with correlation coefficient > 0.99. The interday accuracy ranged from −9.03% to 5.99% (RSD < 7.84%), and the intraday accuracy from −5.15% to 8.56% (RSD < 6.90%). NX-5948 was demonstrated to be stable under the present storage conditions. After validation, the method was successfully applied for the quantification of NX-5948 in beagle dog plasma after oral and intravenous administration of the NX-5948.
研究领域:
药物分析
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生物制药
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临床药理学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2020
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IF 6.205
Yiqing Yang,Hongying Gao,Xiuyun Sun,Yonghui Sun,Yueping Qiu,Qinjie Weng,Yu Rao
The BCR–ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR–ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR–ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR–ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-type and T315I-mutated BCR–ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.
研究领域:
肿瘤学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2026
·
IF 4.7
Jingjie Zhang,Yanmin Chen,Zhenyi Lin,Changhua Xu,Lijuan Zhu,Chuan Zhang
Androgenetic alopecia (AGA), a prevalent form of hair loss primarily affecting younger individuals, remains a significant therapeutic challenge due to the lack of effective treatments. The pathogenesis of AGA is driven by the interaction between androgen receptors (AR) and androgens, as well as by dysregulation of the follicular ecological niche resulting from excessive reactive oxygen species (ROS) and insufficient vascularization in the perifollicular microenvironment. Given the multifactorial nature of AGA, a multi-target therapeutic strategy, rather than a single-target approach, has emerged as a promising method to enhance treatment efficacy. In this study, we developed nanoliposomes (NLPs) formulation by self-assembling AR-PROTAC (ARV110) and NFKBIZ siRNA (siNFKBIZ) into nanoparticles, followed by surface modification with liposomes. This design simultaneously targets AR degradation and alleviates oxidative stress, thereby improving the follicular microenvironment and promoting hair regrowth. The NLPs formulation effectively addresses the challenge of delivering payloads to keratinocytes (HaCaT), facilitates efficient skin penetration, scavenges excess ROS, and inhibits the inflammatory response in hair follicles. Additionally, NLPs downregulate AR protein expression to modulate hair growth-associated signaling pathways, achieving a multimodal synergistic therapeutic effect for AGA. Our design offers an effective multi-target strategy for AGA, resulting in enhanced therapeutic effects for hair loss treatment.
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PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2026
·
IF 14.6
Xiaolan Xu,Chenxia Bai,Jiqiang Qu,Yinghou Wang,Qing Yan,Xiaohua Ran,Jiaming Zhang,Yangyang Liu,Jing Li,Lianghui Peng,Zhihui Sun,Guozheng Liu,Tianhong Zhang,Zhonggui He,Jin Sun,Jingyi Zhang,Jingdong Xiao,Qikun Jiang
The therapeutic potential of DNA-damaging agents like the topoisomerase I inhibitor exatecan (Exa) is frequently hindered by two major limitations: unfavorable physicochemical properties and intrinsic cellular defense mechanisms such as DNA repair pathways. To address these challenges, four albumin-binding prodrugs (C8-Exa, C12-Exa, C14-Exa, and C16-Exa) were developed by conjugating Exa with saturated fatty acids of varying chain lengths as albumin-binding motifs, integrated with a valine-citrulline dipeptide linker for cathepsin B (CTSB)-responsive activation, enabling their formulation into albumin nanoparticles (ANPs). Structure–activity relationship studies revealed a pseudo-parabolic trend in both albumin affinity and CTSB responsiveness as a function of fatty-acid chains, with C14-Exa ANPs achieving the optimal balance. C14-Exa ANPs exhibited superior albumin affinity, drug release kinetics, colloidal stability, and pharmacokinetics, achieving stronger tumor regression. To further amplify DNA-damaging therapeutics, hybrid ANPs (C14-ARV ANPs) were engineered by co-assembling C14-Exa with the BRD4-targeting PROTAC ARV-825, which acts through an “empty extinguisher” mechanism to disable DNA repair defenses. This dual-functional nanoplatform synergistically suppresses tumor growth by combining a structure-optimized Exa prodrug that ensures efficient DNA damage induction with ARV-825-mediated BRD4 degradation, which disrupts DNA damage repair progression and promotes apoptosis. This work establishes a rational nanoplatform design to enhance DNA damage-amplified cancer therapy.
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高影响因子
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