JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Ziqi Pan,Zhiying Qin,Ziyu Qian,Gui Han,Mengqi Sun,Yueying Bian,Tinghui Jin,Yuan Yin,Yongjie Zhang,Zhanbo Wang,Zhangjian Huang,Xijing Chen,Shentian Zhuang,Di Zhao
Abstract Cisplatin is a cornerstone chemotherapeutic for ovarian cancer, yet its clinical utility is constrained by severe systemic toxicity and acquired drug resistance. Here we report a novel platinum (IV) prodrug, US-CIS-OH, generated by conjugating cisplatin with ursolic acid (UA), a natural pentacyclic triterpenoid with intrinsic anticancer activity. US-CIS-OH, markedly increases platinum uptake and DNA platination in cisplatin-resistant ovarian cancer cells, induces S- and G2/M-phase arrest and apoptosis, and suppresses cell migration and clonogenic growth. Chemoproteomic profiling indicates that US-CIS-OH directly engages the XPO1 and PARP1, and is associated with increased levels of cleaved caspase-3. In a cisplatin-resistant ovarian cancer xenograft model, US-CIS−OH elicits marked tumor regression with minimal toxicity. This dual-acting system achieves synergistic effects from both the intact conjugated and bioreductively released cisplatin. Collectively, these results identify US-CIS−OH as a promising next-generation platinum-based agent to overcome cisplatin resistance by enhancing DNA damage, promoting apoptosis, and limiting metastatic traits.
✓ 已验证
DOI
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2026
·Vol. 87
·期 2
·e70265
·
IF 4.2
Jiao Li,Mingrong Song,Yifan Bu,Jing Chen
Vascular dementia (VD) is a cerebrovascular disease-associated cognitive disorder characterized by chronic neuroinflammation. Cinnamic acid (CA), a natural aromatic carboxylic acid, has been demonstrated to mitigate neurological dysfunction. In this study, a two-vessel occlusion (2-VO) rat model was established, and the rats were treated with CA at doses of 45 mg/kg and 90 mg/kg via intragastric gavage. CA treatment significantly restored cognitive function in 2-VO rats, which was attributed to the reduction of neuronal apoptosis. Furthermore, CA administration downregulated the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the hippocampal tissues, while upregulating the expressions of arginase-1 (Arg-1), found in inflammatory zone 1 (Fizz1), and chitinase 3-like 3 (YM-1). These observations suggest that CA promotes the alternatively activated (M2) polarization of microglia in hippocampal tissues. To simulate the neuroinflammatory environment in vitro, BV2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. CA pretreatment promotes M2 polarization in OGD/R-induced BV2 cells, opposing OGD/R-driven M1 polarization in these cells. Importantly, network pharmacology analysis identified poly (ADP-ribose) polymerase 1 (PARP1) as a downstream target of CA. PARP1 expression was upregulated in the hippocampal tissues of 2-VO rats and OGD/R-induced BV2 cells, while CA treatment significantly reduced PARP1 expression. Notably, exogenous PARP1 reversed the CA-induced promotion of the microglial M2 phenotype, as evidenced by increased iNOS expression and decreased Arg-1 expression. In conclusion, CA targets PARP1 to promote the M2 polarization of microglia, thereby alleviating neuroinflammation and contributing to the recovery of neurological function in 2-VO rats.
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.5
Dongshan Chen,Yuan Zeng,Yuanchen Liu,Haochen Cui,Yixuan Zhao,Lei Yan,Yuanwei Zang
Clear cell renal cell carcinoma (ccRCC) progression is closely associated with pro-tumorigenic neutrophil extracellular traps (NETs) within the tumor microenvironment; however, the upstream molecular mechanisms remain poorly defined. Through integrated multi-omics analysis of ccRCC cohorts, we identified ITPKB as a key downregulated gene associated with NET formation. Subsequent functional validation, including dual-luciferase reporter assays, confirmed that ITPKB is a direct target of the miR-301b-3p. Mechanistically, the loss of ITPKB prevents the ubiquitination-mediated degradation of PARP1, leading to its stabilization and accumulation. Stabilized PARP1 acts as a transcriptional co-activator for NF-κB, triggering a robust secretion of IL-8, which recruits neutrophils and induces their transformation into NETs. These NETs facilitate tumor cell migration and adhesion while conferring resistance to tyrosine kinase inhibitors (sunitinib and sorafenib) and anti-PD-1 therapy. In vivo, the treatment with DNase1 to disrupt NETs effectively reversed this therapeutic resistance. Our findings unveil the miR-301b-3p/ITPKB/PARP1/IL8/NETs axis as a novel mechanistic link between tumor-intrinsic signaling and neutrophil-driven immunosuppression, providing a solid experimental foundation for developing combination therapeutic strategies for advanced ccRCC.
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
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
·
分子生物学
·
药理学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Ma Luyu,Zhong Mingzhe,Chang Yingxuan,Luo Mingjin,Liu Xinyan,Ge Xiaofan,Xu Sitian,Zhang Yun,Liu Ziye,Xiang Hua,Luo Guoshun
Dual inhibition of Polθ and PARP1 represents a
promising
precision therapy strategy for HR-deficient tumors. While our first-generation
Polθ/PARP1 dual inhibitor 4 provided proof-of-concept,
its further development was hampered by poor selectivity over PARP2
and metabolic instability. Herein, we describe a structure-guided
optimization that pioneers the integration of PARP1-selective pharmacophores.
This effort culminated in the discovery of compound PP-048 ( 23 ), a second-generation dual inhibitor with single-digit
nanomolar potency against Polθ and PARP1 (IC 50 =
4.9 nM and 6.8 nM, respectively) and >226-fold selectivity over
PARP2,
PARP3, PARP5a/b, and PARP7. Notably, PP-048 displayed
markedly improved hepatic stability and favorable oral systemic exposure.
In an MDA-MB-436 xenograft model, PP-048 (10 mg/kg) achieved
marked tumor growth inhibition (TGI = 91%) without eliciting the hematologic
toxicity associated with PARP2 inhibition. To our knowledge, PP-048 represents the first reported PARP1-isoform-selective
dual inhibitor, establishing a strategic foundation for development
of this emerging class of inhibitors.
✓ 已验证
产品关联
DOI
高影响因子
LANGMUIR
·
2023
·
IF 3.9
Yuanyuan Ou,Sai Qiao,Ting Li,Xinxin Zheng,Xue Zhao,Lejing Qu,Xinfeng Zhao,Yajun Zhang
Revealing drug–protein interaction is highly important to select a drug candidate with improved drug-like properties in the early stages of drug discovery. This highlights the urgent need to develop assays that enable the analysis of drug–protein interaction with high speed. Herein, this purpose was realized by the development of an affinity chromatographic method with a two-fold higher speed than typical assays like frontal analysis and zonal elution. The method involved synthesis of a stationary phase by immobilizing poly(ADP-ribose) polymerase-1 (PARP1) onto macroporous silica gel through a one-step bioorthogonal reaction, characterization of mutual displacement interaction of two canonical drugs to the immobilized PARP1, determination of the interaction between three (iniparib, rucaparib, and olaparib) drugs and the protein, and validation of these parameters by typical frontal analysis. The numbers of binding sites on the column were (2.85 ± 0.05) × 10–7, (1.89 ± 0.71) × 10–6, and (1.49 ± 0.06) × 10–7 M for iniparib, rucaparib, and olaparib, respectively. On these sites, the association constants of the three drugs to the protein were (9.85 ± 0.56) × 104, (2.85 ± 0.34) × 104, and (1.07 ± 0.35) × 105 M–1. The determined parameters presented a good agreement with the calculation by typical frontal analyses, which indicated that the current continuous competitive frontal analysis method was reliable for determining drug–protein interaction. Application of the methods was achieved by screening tubeimosides I and II as the bioactive compounds against breast cancer in Bolbostemma paniculatum. Their mechanism may be the interference of DNA repair via down-regulating PARP1 and meiotic recombination 11 expressions, thus leading to oncogene mutations and death of cancer cells. The method was high speed since it allowed simultaneous determination of binding parameters between two drugs and a protein with a smaller number of experiments to be performed. Such a feature made the method an attractive alternative for high-speed analysis of drug–protein interaction or the other bindings in a binary system.
研究领域:
药学
·
分析化学
·
药物发现
·
癌症研究
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
Genes
·
2025
·Vol. 16
·期 9
·1037
·
IF 2.8
Zhiyu Wu,Menghuan Xiao,Zelin Gong,Benjie Wang,Wenxin Zhao,Yiyuan Guo,Lu Yang
Objectives: The objectives of this study are to investigate the therapeutic targets and mechanisms of proanthocyanidins in alleviating fluoride-induced liver injury through network pharmacology and animal experimental validation and to explore the medicinal value of grape seed proanthocyanidins.Methods: Potential targets of proanthocyanidins were predicted using databases such as PubChem, SwissTargetPrediction, and GeneCards, and disease-related targets of fluoride-induced liver injury were retrieved to identify common targets between proanthocyanidins and fluoride-induced liver injury. The STRING database was utilized to construct a protein–protein interaction network, and key targets were analyzed for network topology using Cytoscape software. GO and KEGG enrichment analyses were performed on core target genes to explore the potential molecular mechanisms by which proanthocyanidins alleviate fluoride-induced liver injury. The Genes-miRNA interaction network was generated using Networkanalyst, and the molecular docking results between active components and key targets were validated using the CB-Dock2 visualization tool. In the academic context, a rat model of chronic fluoride poisoning was successfully established by means of intragastric administration of sodium fluoride. The protein expression levels of p-mTOR, p-p70s6, p62, LC3-II, and PARP1 in rat liver tissues were detected via Western blot analysis.Results: Network pharmacological analysis successfully identified 96 key genes, through which proanthocyanidins mitigate fluoride-induced liver injury. KEGG enrichment analysis predicted that proanthocyanidins mainly exert their therapeutic effects through the mTOR signaling pathway. The molecular docking results further demonstrated strong binding affinities between proanthocyanidins and key targets, including mTOR and PARP1. The in vivo experimental results indicate that, compared with the control group, the protein expression levels of p-mTOR, p-p70s6k, and p62 in the liver tissues of rats exposed to sodium fluoride significantly increase. Conversely, the protein expression levels of LC3-II and PARP1 significantly decrease (p< 0.05). The outcome of liver intervention with proanthocyanidins is exactly the opposite.Conclusions: Proanthocyanidins can effectively alleviate fluoride-induced liver injury, potentially by regulating the mTOR signaling pathway, autophagy, and apoptosis mechanisms. This study provides valuable insights into the protective effects of proanthocyanidins against fluoride-induced hepatic damage and offers a theoretical basis for further research in this field.
研究领域:
药理学
·
毒理学
·
分子生物学
·
生物信息学
·
营养科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Changrong Wang,Xiaoguang Shi,Huijuan Song,Chuangnian Zhang,Xiaoli Wang,Pingsheng Huang,Anjie Dong,Yumin Zhang,Deling Kong,Weiwei Wang
Immunotherapy has revolutionized cancer treatment; however, only a limited portion of patients show responses to currently available immunotherapy regimens. Here, we demonstrate that RNA interference (RNAi) combined with immunogenic chemotherapy can elicit potent antitumor immunity against melanoma. Specially, we developed cationic polymer-lipid hybrid nanovesicles (P/LNVs) as a new delivery system for doxorubicin and small interfering RNA (siRNA) with extensive cytotoxicity and gene silencing efficiency towards B16 cells. The deployment of doxorubicin-loaded P/LNVs augmented the expression and presentation of endogenous tumor antigens directly in situ by inducing the immunogenic cell death of B16 cells through poly(ADP-ribose) polymerase 1-dependent (PARP1) apoptosis pathway; thereby, eliciting remarkable antitumor immune responses in mice. Leveraging dying B16 cells as a vaccination strategy in combination with RNAi-based programmed cell death ligand 1 (PD-L1) knockdown showed efficacy in both prophylactic and metastasis melanoma settings. Strikingly, PD-L1 blockade synergized with a sub-therapeutic dose of doxorubicin triggered robust therapeutic antitumor T-cell responses and eradicated pre-established tumors in 30% of mice bearing B16 melanoma. Our findings indicated that this combination treatment provided a new powerful immunotherapy modality, characterized by markedly increased infiltration of effector CD8 + T cells and effective alleviation of the immunosuppressive microenvironment in tumors. P/LNVs is a versatile and highly scalable carrier that can enable a broad combination of nanomedicine and RNAi, providing new therapeutic strategies for advanced cancers.
研究领域:
癌症治疗
·
纳米技术
·
免疫学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Engineering
·
2024
·
IF 10.1
Ruogu Qi,Shanshan Wang,Jiayi Yu,Tianming Lu,Zhiqiang Bi,Weibo Liu,Yuanyuan Guo,Yong Bian,Jianliang Shen,Xuesong Zhang,Wenhao Hu
Multiple myeloma (MM) is the second most prevalent hematological malignancy. Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy. This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy, which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes, termed T-PB@M. The results from our investigations highlight the considerable bone affinity of T-PB@M, both in vitro and in vivo . Additionally, this material demonstrated a capability for drug release triggered by low pH conditions. Moreover, T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose) polymerase 1 (PARP1)–Caspase-3–B-cell lymphoma-2 (Bcl-2) pathway in MM cells. Notably, T-PB@M preferentially targeted bone-involved sites, thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice. Therefore, this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.
研究领域:
肿瘤学
·
纳米技术
·
药理学
·
细胞生物学
✓ 已验证
DOI
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 9
·1837
·
IF 7.675
Yanling Lin,Qinzhi Zhang,Baofu Xie,Haiyang Jiang,Jianzhong Shen,Shusheng Tang,Chongshan Dai
Chelerythrine (CHE) is a majorly harmful isoquinoline alkaloid ingredient inChelidonium majusthat could trigger potential hepatotoxicity, but the pivotal molecular mechanisms remain largely unknown. In the present study, CHE-induced cytotoxicity and the underlying toxic mechanisms were investigated using human HepG2 cells in vitro. Data showed that CHE treatment (at 1.25–10 μM)-induced cytotoxicity in HepG2 cells is dose-dependent. CHE treatment increased the production of ROS and induced oxidative stress in HepG2 cells. Additionally, CHE treatment triggered the loss of mitochondrial membrane potential, decreased the expression of mitochondrial complexes, upregulated the expression of Bax, CytC, and cleaved-PARP1 proteins and the activities of caspase-9 and caspase-3, and downregulated the expression of Bcl-XL, and HO-1 proteins, finally resulting in cell apoptosis. N-acetylcysteine supplementation significantly inhibited CHE-induced ROS production and apoptosis. Furthermore, CHE treatment significantly downregulated the expression of phosphorylation (p)-Akt (Ser473), p-mTOR (Ser2448), and p-AMPK (Thr172) proteins in HepG2 cells. Pharmacology inhibition of Akt promoted CHE-induced the downregulation of HO-1 protein, caspase activation, and apoptosis. In conclusion, CHE-induced cytotoxicity may involve the inhibition of Akt pathway and the activation of oxidative stress-mediated mitochondrial apoptotic pathway in HepG2 cells. This study sheds new insights into understanding the toxic mechanisms and health risks of CHE.Keywords:chelerythrine;oxidative stress;apoptosis;mitochondrial apoptotic pathway;Akt pathway
研究领域:
药理学
·
毒理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）