Targeting the TRIB3-MYC axis in cancer: mechanistic insights and therapeutic disruption strategies.

The oncogenic transcription factor MYC drives proliferation, metabolism, and therapy resistance in the majority of human cancers, yet its large, nuclear protein-protein interface has long frustrated direct drug discovery. A pivotal breakthrough was the identification of Tribbles pseudokinase 3 (TRIB3) as a high-affinity scaffold that binds the helix-loop-helix/leucine zipper region of MYC, blocks the E3-ubiquitin-ligase, UBE3B, from tagging critical lysines, and thereby prolongs MYC protein half-life while enhancing MYC-MAX transcriptional output. This review integrates structural, biochemical, and in vivo data to show how genetic deletion or pharmacological eviction of TRIB3 collapses MYC levels, silences its gene program, and suppresses tumor growth in B-cell lymphomas and selected solid tumors.

Correction: Multi-pronged molecular insights into flavonoid-mediated inhibition of squalene epoxidase: a pathway to novel therapeutics.

[This corrects the article DOI: 10.1039/D4RA09076D.].

3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitory Activity of Padina pavonia Terpenoids: An Integrated In Vitro and In Silico Exploration.

The inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMGCR) activity carries considerable therapeutic significance, prompting the investigation of novel inhibitors to tackle associated health conditions and improve patient care. Seeking non statin scaffolds, we provide the first integrated evaluation of six terpenoids isolated from the brown alga Padina pavonia, expanding the species' chemical repertoire and establishing their activity against HMGCR. We have previously shown the anti-hyperlipidemia activity of P.

Breaking the oncogenic alliance: advances in disrupting the MTDH-SND1 complex for cancer therapy.

Metadherin (MTDH/AEG-1/LYRIC) partners with Staphylococcal Nuclease Domain-Containing Protein 1 (SND1) to form an oncogenic hub that drives proliferation, survival and metastasis in many tumors. Interrupting this interaction dampens pivotal pathways-including NF-κB, PI3K/Akt and Wnt/β-catenin-and simultaneously promotes SND1 degradation, yielding broad antitumor effects. This review consolidates current knowledge of the MTDH-SND1 axis and highlights preclinical studies showing that genetic knock-out or pharmacologic blockade of the complex can sharply reduce primary growth and metastatic spread.

Mechanistic basis of aldose reductase inhibition by phenolics from : experimental insights and computational validation.

Unlabelled: This study explores the inhibitory potential of phenolic compounds derived from against aldose reductase (AR), a key enzyme implicated in diabetic complications. Among the six tested compounds, salvianolic acid B exhibited the strongest inhibitory activity, with an IC of 1.90 ± 0.

Sustainable leads for hypoxic tumor therapy: allosteric selective inhibition of carbonic anhydrase IX by abietane-type resin acids.

Carbonic anhydrase IX (CA IX) helps hypoxic tumors maintain the acidic extracellular milieu that drives invasion and therapy resistance, making it an attractive but still under-exploited drug target. Here we report that four abietane-type resin acids-callitrisic, levopimaric, palustric and pimaric acids-act as potent, non-competitive and CA IX-selective inhibitors. Virtual screening of 2400 natural products, followed by AutoDock Vina, positioned the rigid diterpenoid cores in a hydrophobic cleft that flanks-but does not overlap-the catalytic zinc.

Tackling tumor hypoxia: advances in breaking the oncogenic HIF-1α-p300/CBP alliance.

The ability of tumor cells to survive under low-oxygen conditions is largely attributed to the hypoxia-inducible factor-1 (HIF-1) pathway, in which HIF-1α forms a functional complex with the transcriptional co-activators p300/CBP. This interaction drives the expression of genes that promote angiogenesis, metabolic reprogramming, and immune evasion and correlates with advanced disease and poor outcomes in diverse cancer types. In recent years, extensive efforts have sought to disrupt the HIF-1α-p300/CBP axis, leveraging strategies that include blocking protein-protein binding, inhibiting acetyltransferase activity, and modulating post-translational modifications that stabilize HIF-1α.

Targeting the ATG12-ATG3 protein-protein interaction: From structural insights to therapeutic opportunities in autophagy modulation.

Autophagy sustains cellular metabolism, shapes immune signaling and, when dysregulated, contributes to cancer progression and cytokine-storm syndromes. A crucial catalytic step is conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, driven by direct binding of the E2-like enzyme autophagy-related protein 3 (ATG3) to the ubiquitin-like protein autophagy-related protein 12 (ATG12). Disrupting this ATG12-ATG3 protein-protein interaction (PPI) could silence both the degradative and secretory arms of autophagy with high pathway selectivity.

Uncoupling toxic NO signaling: Progress, challenges, and therapeutic promise of disrupting the PSD-95/nNOS protein-protein interaction.

The interaction between postsynaptic density-95 (PSD-95) and neuronal nitric-oxide synthase (nNOS) forms a signaling hub that couples N-methyl-d-aspartate receptor (NMDAR) calcium influx to bursts of neurotoxic nitric oxide. Disrupting this protein-protein interaction (PPI) offers a strategy to suppress pathological NO production while sparing normal synaptic transmission-an advantage unattainable with channel blockers or active-site nNOS inhibitors. Over the past two decades, cell-penetrant peptides such as nerinetide (Tat-NR2B9c) have validated the target from rodent stroke models to phase-III clinical trials, while bivalent constructs achieve low-nanomolar affinity and extended brain exposure.

Breaking the oncogenic link: BCL10-MALT1 disruption as a precision strike against NF-κB-driven lymphomas.

The CARMA1-BCL10-MALT1 (CBM) complex plays a pivotal role in mediating antigen receptor-induced activation of NF-κB, a pathway critical for lymphocyte survival and proliferation. In aggressive lymphoid malignancies such as activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), oncogenic mutations drive constitutive CBM complex activation, leading to chronic NF-κB signaling and treatment resistance. Traditional therapeutic approaches have focused on inhibiting MALT1's protease activity; however, these strategies incompletely suppress CBM-driven signaling and may provoke immune-related toxicities by selectively impairing regulatory T cell function.

Mechanism-Based Allosteric Inhibition of PTP1B by Prenylated Flavonoids from Glycyrrhiza echinata: In Vitro Experiments and in Silico Validation.

A phytochemical investigation of Glycyrrhiza echinata led to the isolation and structural characterization of twelve phenolic compounds. An in silico target fishing analysis identified protein tyrosine phosphatase 1B (PTP1B) as a potential biological target for these phytochemicals, prompting an in vitro evaluation of their PTP1B inhibitory activities. Gancaonin Q and licoflavone C exhibited notably low IC₅₀ values (1.

Modulating UDP-glucuronosyltransferase activity: Mechanisms, clinical implications, therapeutic strategies, and future directions in drug development.

UDP-glucuronosyltransferases (UGTs) are essential enzymes in the phase II metabolism of endogenous and exogenous compounds, playing a critical role in detoxification, drug metabolism, and clearance. Their function is crucial for the pharmacokinetics of numerous therapeutic agents, but UGT inhibition can result in altered drug metabolism, increased toxicity, or reduced efficacy. This review explores the mechanisms of UGT inhibition, its implications for drug metabolism and pharmacokinetics, and the clinical relevance of such inhibition in the context of drug-drug interactions (DDIs).

Mechanism of alkaloid-based inhibition of aldose reductase: Computational perspectives and experimental validations.

Excessive aldose reductase activity drives the polyol-pathway damage that underlies diabetic cataract, neuropathy and nephropathy, yet few safe, potent AR inhibitors have reached the clinic. Here we integrated virtual screening, atomistic simulation and enzymology to evaluate six natural alkaloids-calycanthine, rutaecarpine, glaucine, sparteine, berbamine and tetrandrine-as prospective AR antagonists. A 2500-compound AutoDock Vina screen singled out these scaffolds for high predicted affinity (≤ - 7.

Computationally Guided Structural Modification of Centaureidin: A Novel Approach for Enhancing Antioxidant and Antitumor Activities for Drug Development.

The development of novel therapeutic drugs with enhanced efficacy has gained significant attention in recent years. In this study, we aimed to enhance the radical scavenging and antitumor activities of centaureidin through computationally guided structural modifications. Centaureidin was initially isolated through extensive phytochemical fractionation from Centaurea scoparia.

Coumarin-Based Allosteric Inhibition of PTP1B: A Potential Strategy for Metabolic Regulation.

Protein Tyrosine Phosphatase 1B (PTP1B) is a key metabolic regulator and a promising therapeutic target for type 2 diabetes and obesity. This study evaluated the inhibitory potential of four coumarins-Bergapten, Imperatorin, Xanthotoxol, and Isopimpinellin, isolated from Ammi majus-through in silico and in vitro approaches. Molecular docking and molecular dynamics (MD) simulations identified Bergapten and Imperatorin as the most stable binders, forming key π-π stacking interactions with Phe280 and Phe196.

Phenolic-based allosteric inhibition of PTP1B: unlocking new therapeutic potential for metabolic disorders.

Protein tyrosine phosphatase 1B (PTP1B) plays a critical role in insulin signaling and is associated with various metabolic diseases, including type 2 diabetes. In this study, we investigated the inhibitory potential of five phenolic compounds isolated from Tamarix aphylla against PTP1B. Using molecular docking, molecular dynamics (MD) simulations, and ADMET analysis, we assessed the binding modes, stability, and pharmacokinetic properties of these compounds.

A Multifaceted Mechanistic Approach to Assess the Inhibitory Potential of Broccoli-Derived Glucosinolates Against Tumor-Associated Carbonic Anhydrase IX.

Hypoxia-induced carbonic anhydrase IX (CA IX) is a clinically validated anticancer target; yet, few natural, isoform-selective inhibitors have been described. We isolated three glucosinolates-glucoraphanin, 1,4-dimethoxyglucobrassicin, and 4-methoxyglucobrassicin-from Brassica oleracea and interrogated their CA IX inhibitory potential through an integrated experimental-computational workflow. Enzyme assays revealed mixed-type inhibition with nanomolar potency (IC₅₀ = 65-221 nM), while counterscreens against housekeeping CA I/II demonstrated > 40-fold selectivity.

Watercress-derived glucosinolates as potential allosteric PTP1B inhibitors: a dual in silico and in vitro study on insulin signaling modulation.

This study investigates the inhibitory potential of four glucosinolates-glucoerucin, glucoiberin, gluconasturtiin, and glucotropaeolin-isolated from watercress (Nasturtium officinale) against Protein Tyrosine Phosphatase 1B (PTP1B), a key regulator of insulin signaling. Molecular docking, molecular dynamics (MD) simulations, and MM/PBSA free energy calculations identified glucoerucin (-17.18 ± 3.

β-Glucuronidase Inhibition in Drug Development: Emerging Strategies for Mitigating Drug-Induced Toxicity and Enhancing Therapeutic Outcomes.

β-glucuronidase (βG) is a critical enzyme involved in the hydrolysis of glucuronide conjugates, significantly influencing drug metabolism, detoxification processes, and enterohepatic circulation. Although essential for maintaining physiological homeostasis, dysregulated βG activity has been implicated in diverse pathological conditions, including drug-induced toxicity, inflammation, and hormone-dependent cancers. Specifically, microbial βG expressed by gut microbiota can reactivate glucuronide-conjugated drugs, leading to adverse reactions through increased drug toxicity and reduced therapeutic efficacy.

Repurposing FDA-approved allosteric drugs as non-competitive inhibitors of human UGTs: An integrated computational study and biochemical validation.

UDP-glucuronosyltransferases (UGTs) catalyze a major detoxification route for xenobiotics, yet chemical tools that modulate their activity are virtually absent and the possibility of allosteric regulation is largely unexplored. We combined ligand-based target prediction, structure-based docking, long-timescale molecular dynamics and MM/PBSA free-energy calculations to search the pharmacopeia for hidden UGT modulators. Six FDA-approved allosteric drugs were screened against the catalytic domains of UGT1A1, 1A9, 2B7 and 2B15.

Disrupting the Hsp90-Cdc37 axis: a selective strategy for targeting oncogenic kinases in cancer.

Heat shock protein 90 (Hsp90) is a crucial molecular chaperone responsible for the maturation and stabilization of a wide range of client proteins, many of which are key drivers of oncogenic signaling. While traditional Hsp90 inhibitors targeting its ATPase activity have demonstrated antitumor potential, their clinical progress has been limited by issues such as low selectivity, toxicity, and the induction of cytoprotective heat shock responses. An alternative strategy focuses on disrupting the specific protein-protein interaction between Hsp90 and its kinase-specific co-chaperone, cell division cycle 37 (Cdc37), thereby selectively destabilizing oncogenic kinases without broadly impairing chaperone function.

Repurposing dual-C-prenylated flavonoids as potent allosteric inhibitors of PTP1B: Integrated phytochemical, enzymological, and in silico evidence.

Protein-tyrosine phosphatase 1B (PTP1B) is a master negative regulator of insulin and leptin signaling, yet clinically useful inhibitors remain elusive. Guided by a repurposing strategy, we investigated Tephrosia villosa as a natural source of PTP1B modulators. Chromatographic fractionation of the aerial parts afforded nine flavonoids and related phenolics, whose structures were elucidated by spectroscopic tools.

Mechanistic Insights into Polyphenols-mediated Squalene Epoxidase Inhibition: Computational Models and Experimental Validation for Targeting Cholesterol Biosynthesis.

Squalene epoxidase is a key enzyme in sterol biosynthesis, particularly in cholesterol metabolism. Its inhibition has emerged as a promising therapeutic strategy for metabolic disorders, hypercholesterolemia, and certain infections. Herein, we investigated the SQLE inhibitory potential of six polyphenolic compounds, identified through in silico virtual screening of a large natural phenolic library and selected for high predicted binding affinity and structural diversity.

Multi-pronged approaches to the mechanism-based inactivation of aldose reductase by natural coumarins: molecular insights and experimental validation.

In this study, we measured the inhibitory potential of six coumarins against aldose reductase using both computational and experimental approaches. Molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations identified auraptene, marmesin, and isopimpinellin as the most promising inhibitors, with binding affinities of ΔG = -34.88, -29.