Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: March 1, 2024

Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting have attracted considerable interest in recent years. Molecular hybridization, advantage of simplified pharmacokinetics and drug-drug interactions, emerged one important avenues for discovering potential drugs. This study aimed construct by hybridization investigate their antitumor activity mechanism. 26 quinazoline-2-indolinone derivatives were obtained molecular structure–activity relationship was analyzed MTT, vitro docking. The biological evaluation compound 8 performed transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA immunohistochemistry. Here, we employed methods a series inhibitors. Encouragingly, representative exhibited enzymatic IC50 value 9.11 nM 10.41/16.99/37.53-fold relative biochemical selectivity PI3Kβ/γ/δ, respectively. Moreover, effectively suppressed viability B16, HCT116, MCF-7, H22, PC-3, A549 cells (IC50 values: 0.2 μM ∼ 0.98 μM), dramatically inhibited proliferation migration NSCLC cells, well induced mitochondrial apoptosis through PI3K/Akt/mTOR pathway. Importantly, demonstrated potent vivo anti-tumor non-small cell lung cancer mouse models without visible toxicity. presented new avenue development provided solid foundation novel QHIDs future therapies treatment NSCLC.

Language: Английский

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Carrier-free self-assembled nanomedicine based on celastrol and galactose for targeting therapy of hepatocellular carcinoma via inducing ferroptosis

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116183 - 116183

Published: Feb. 5, 2024

Language: Английский

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Cancer resistance and metastasis are maintained through oxidative phosphorylation

Cancer Letters, Journal Year: 2024, Volume and Issue: 587, P. 216705 - 216705

Published: Feb. 18, 2024

Language: Английский

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Design and synthesis of a novel β-anhydroicartin derivative targeting tumor cell mitochondria based on the regulation of p16INK4a and its in vitro biological activity evaluation

Journal of Asian Natural Products Research, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: April 10, 2025

Based on the regulation of β-anhydroicaritin stability p16INK4a encoded by CDKN2A gene, nine novel triphenylphosphine derivatives targeting tumor cell mitochondria were synthesized. Compound 13 increased ability to inhibit lung cancer A549 cells 24 times compared with 5-fluorouracil. Biological studies have shown that compound significantly promotes early apoptosis and induces mitochondrial dysfunction in cells. Further showed arrested 73% G0/G1 phase, preventing from entering DNA synthesis phase. In summary, is expected be developed as a new targeted anti-tumor drug.

Language: Английский

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A review of the pathogenesis of mitochondria in breast cancer and progress of targeting mitochondria for breast cancer treatment

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 15, 2025

With breast cancer being the most common tumor among women in world today, it is also leading cause of cancer-related deaths. Standard treatments include chemotherapy, surgery, endocrine therapy, and targeted therapy. However, heterogeneity, drug resistance, poor prognosis highlight an urgent need for further exploration its underlying mechanisms. Mitochondria, highly dynamic intracellular organelles, play a pivotal role maintaining cellular energy metabolism. Altered mitochondrial function plays critical various diseases, recent studies have elucidated pathophysiological mechanisms carcinogenesis. This review explores dysfunction pathogenesis assesses potential mitochondria-targeted therapies.

Language: Английский

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Bruceine A Inhibits Cell Proliferation by Targeting the USP13/PARP1 Signalling Pathway in Multiple Myeloma

Basic & Clinical Pharmacology & Toxicology, Journal Year: 2025, Volume and Issue: 136(5)

Published: March 28, 2025

ABSTRACT Multiple myeloma (MM) is an incurable hematologic malignancy, driving significant interest in the discovery of novel therapeutic strategies. Bruceine A (BA), a tetracyclic triterpene quassinoid derived from Brucea javanica , has shown anticancer properties by modulating multiple intracellular signalling pathways and exhibiting various biological effects. However, specific pharmacological mechanisms which it combats MM remain unclear. In this study, we identified USP13 as potential target BA. We observed increase expression patients with MM, was strongly associated poorer prognosis. Furthermore, enhanced can stimulate cell proliferation both vitro vivo. Mass spectrometry analysis, combined co‐immunoprecipitation ubiquitination experiments, revealed PARP1 critical downstream USP13. stabilize protein through deubiquitination, promoting PARP1‐mediated DNA damage repair (DDR) facilitating progression. Notably, utilized lines, Patient‐Derived Tumour Xenograft model, 5TMM3VT mouse model to determine effects BA on progression, revealing its USP13/PARP1 disrupt DDR cells. conclusion, these findings suggest that inhibiting USP13/PARP1‐mediated might be promising strategy for MM.

Language: Английский

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Responsive ROS‐Augmented Prodrug Hybridization Nanoassemblies for Multidimensionally Synergitic Treatment of Hepatocellular Carcinoma in Cascade Assaults

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Abstract The rapid deterioration and progression of hepatocellular carcinoma (HCC) is intimately associated with copper ion overload, integrating the cuproptosis mechanism for treatment HCC presents a promising prospect. Nevertheless, cell death complexity renders efficient removal all cells insufficient solely relying on pathway. Herein, GSH‐responsive prodrug hybridization nanoassembly CA‐4S 2 @ES‐Cu exploited, which targets delivery ions to mitochondria via Elesclomol, contributing mitochondrial dysfunction evoking cuproptosis. Simultaneously, depletes GSH release CA‐4, disrupting microtubule function suppressing proliferation angiogenesis, realize dual attack against ion‐mediated metastasis HCC. Furthermore, both in mouse model synergistically elicit oxidative stress amplify effect activated immunogenetic initiate vigorous antitumor immune response cascade assault modality. Conclusively, multilevel synergistic penetrates limitations single therapy implements multidimensional targeted

Language: Английский

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Pyrocurzerenone suppresses human oral cancer cell metastasis by inhibiting the expression of ERK1/2 and cathepsin S proteins

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(16)

Published: Aug. 1, 2024

Pyrocurzerenone is a natural compound found in Curcuma zedoaria and Chloranthus serratus. However, the anticancer effect of pyrocurzerenone oral cancer remains unclear. Using MTT assay, wound healing transwell assay western blot analysis, we investigated impact on antimetastatic activity, as well critical signalling pathways that underlie processes cell lines SCC-9, SCC-1 SAS this work. Our findings suggested inhibits migration invasion ability lines. Furthermore, phosphorylation ERK1/2 had significant inhibitory effects SCC-9 Combining inhibitors with decreased activity We also expressed level cathepsin S under treatment. This study showed reduced expression proteins S, suggesting it could be valuable treatment to inhibit human metastasis.

Language: Английский

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ResisenseNet hybrid neural network model for predicting drug sensitivity and repurposing in breast Cancer

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 13, 2024

Breast cancer remains a leading cause of mortality among women worldwide, with drug resistance driven by transcription factors and mutations posing significant challenges. To address this, we present ResisenseNet, predictive model for sensitivity resistance. ResisenseNet integrates factor expression, genomic markers, drugs, molecular descriptors, employing hybrid architecture 1D-CNN + LSTM DNN to effectively learn long-range temporal patterns from amino acid sequences data. The demonstrated exceptional accuracy, achieving validation accuracy 0.9794 loss value 0.042. Comprehensive included comparisons state-of-the-art models ablation studies, confirming the robustness developed architecture. has been applied repurpose existing anticancer drugs across 14 different cancers, focus on breast cancer. Among malignancies studied, targeting Low-grade Glioma (LGG) Lung Adenocarcinoma (LUAD) showed increased as per ResisenseNet's assessment. Further evaluation predicted sensitive revealed that had no prior history activity against These target key signaling pathways involved in cancer, presenting novel therapeutic opportunities. addresses filtering ineffective compounds enhancing chemotherapy In vitro studies provide valuable insights into prognosis, contributing improved treatment strategies.

Language: Английский

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The quassinoids bruceines A–M: pharmacology, mechanism of action, synthetic advance, and pharmacokinetics—a review

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2024, Volume and Issue: 397(12), P. 9417 - 9433

Published: July 10, 2024

Language: Английский

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