Search Results (214)

Wee1-like protein kinase 2 (WEE2) is an oocyte-specific kinase that regulates meiotic arrest and fertilization. Its largely restricted expression in female germ cells and absence in somatic tissues make it a highly selective target for reproductive health interventions. Despite its central role in human fertility, no clinically approved WEE2 modulator is available. In this study, we employed an integrated in silico approach that combines structure-based virtual screening, molecular dynamics (MD) simulations, and MM-PBSA free-energy calculations to identify repurposed drug candidates with potential WEE2 inhibitory activity. Screening of ~3800 DrugBank compounds against the WEE2 catalytic domain yielded ten high-affinity hits, from which Midostaurin and Nilotinib emerged as the most mechanistically relevant based on kinase-targeting properties and pharmacological profiles. Docking analyses revealed strong binding affinities (−11.5 and −11.3 kcal/mol) and interaction fingerprints highly similar to the reference inhibitor MK1775, including key contacts with hinge-region residues Val220, Tyr291, and Cys292. All-atom MD simulations for 300 ns demonstrated that both compounds induce stable protein–ligand complexes with minimal conformational drift, decreased residual flexibility, preserved compactness, and stable intramolecular hydrogen-bond networks. Principal component and free-energy landscape analyses further indicate restricted conformational sampling of WEE2 upon ligand binding, supporting ligand-induced stabilization of the catalytic domain. MM-PBSA calculations confirmed favorable binding free energies for Midostaurin (−18.78 ± 2.23 kJ/mol) and Nilotinib (−17.47 ± 2.95 kJ/mol), exceeding that of MK1775. To increase the translational prioritization of candidate hits, we place our structure-based pipeline in the context of modern machine learning (ML) and deep learning (DL)-enabled virtual screening workflows. ML/DL rescoring and graph-based molecular property predictors can rapidly re-rank docking hits and estimate absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities before in vitro evaluation. Full article

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced skin damage. The agouti signaling protein (ASIP) antagonizes the melanocortin-1 receptor (MC1R), hinders melanocyte signaling, and shifts pigmentation toward pheomelanin, promoting UV vulnerability. In this study, we aim to discover compounds that inhibit ASIP–MC1R interaction and effectively preserve eumelanogenic signaling. Methods: The ASIP–MC1R interface-based pharmacophore model from ASIP is implicated in MC1R receptor protein engagement. We performed virtual screening with a validated pharmacophore model for ~4000 compounds curated from ZINCPharmer and applied drug-likeness filters, viz. ADMET and toxicity profiling tests. Further, the screened candidates were targeted for docking to the ASIP C-terminal domain corresponding to the MC1R-binding moiety. Top compounds underwent a 100-nanosecond (ns) run of molecular dynamics (MD) simulations to assess complex stability and persistence of key contacted residues. Results: Sequential triage, including pharmacophore, ADME–toxicity (ADMET), and docking/ΔG, yielded a focused group of candidates against ASIP antagonists with a favorable fit value. The MD run for 100 ns supported pose stability at the targeted pocket. Based on these predictions and analyses, compound ZINC14539068 was screened as a new potent inhibitor of ASIP to preserve α-MSH-mediated signaling of MC1R. Conclusions: Our in silico pipeline identifies ZINC14539068 as a potent inhibitor of ASIP at its C-terminal interface. This compound is predicted to disrupt ASIP–MC1R binding, thereby maintaining eumelanin-biased signaling. These findings motivate experimental validation in melanocytic models and in vivo studies to confirm pathway modulation and anti-melanoma potential. Full article

Chagas disease remains a major public health challenge due to the limited effectiveness and considerable side effects of existing treatments, particularly during the chronic stage. Açaí (Euterpe oleracea) seeds have gained increasing attention as a source of bioactive compounds with potential therapeutic applications. In this study, hydroalcoholic extracts and solvent fractions obtained from açaí seeds were chemically characterized by ESI/MS and HPLC–MS/MS and evaluated for their cytotoxicity and antiparasitic activity against different developmental stages of Trypanosoma cruzi (Y strain). Chemical profiling revealed a predominance of phenolic compounds, particularly catechins and procyanidins, which were identified as major constituents of the hydroalcoholic extract and the ethyl acetate fraction. Cytotoxicity assays performed on murine peritoneal macrophages demonstrated low toxicity, with CC₅₀ values exceeding 500 µg/mL for most samples, indicating a favorable in vitro safety profile. Antiparasitic assays showed weak activity against epimastigote forms; however, significant inhibitory effects were observed against bloodstream trypomastigotes, cell culture-derived trypomastigotes, and intracellular amastigotes. Notably, the hydroalcoholic extract exhibited the highest selectivity against intracellular amastigotes, with a selectivity index greater than 10, fulfilling key criteria proposed by the Drugs for Neglected Diseases initiative (DNDi) for early-stage hit compounds. Flow cytometry analysis showed that both the hydroalcoholic extract and the ethyl acetate fraction induced parasite cell death through late apoptosis-like and necrosis. Together, these findings highlight the antiparasitic potential of E. oleracea seed extracts, particularly against clinically relevant stages of T. cruzi, and support further investigation of these bioproducts as promising candidates for the development of new therapeutic strategies for Chagas disease. Full article

Metabolic reprogramming is a fundamental hallmark and a key driver of malignant tumors. By reshaping glucose, lipid, and amino acid metabolism, as well as mitochondrial function, it sustains the abnormal proliferation and survival of tumor cells, making it a crucial target for anti-tumor therapy. Curcumin, a natural multi-target compound, exhibits unique advantages in intervening in tumor metabolic reprogramming due to its low toxicity and broad-spectrum regulatory properties. In various tumor models, it can directly modulate the activity of key glycolytic enzymes, such as hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2, as well as transporters like glucose transporter 1. Furthermore, it inhibits the expression of proteins related to lipid metabolism, including fatty acid synthase and stearoyl-CoA desaturase 1, while also intervening in amino acid metabolic networks, such as glutaminase and branched-chain amino acid transaminase. Additionally, curcumin targets mitochondrial function and reactive oxygen species balance, creating multi-dimensional intervention effects through various pathways, including the induction of ferroptosis by regulating the SLC7A11/GPX4 axis and modulating gut microbiota metabolism. Its mechanism of action involves the synergistic regulation of key signaling pathways, including phosphoinositide 3-kinase/Akt, NF-κB, AMP-activated protein kinase, and hypoxia-inducible factor-1alpha. Furthermore, its specific effect profile demonstrates significant dependency on cell type and tumor model. This article systematically reviews the regulatory effects of curcumin on these critical metabolic processes and pathways in tumor metabolic reprogramming, revealing its molecular mechanisms in disrupting tumor growth and progression by targeting energy and biosynthetic metabolism. These findings provide a significant theoretical foundation and a preclinical research perspective for the development of natural antitumor drugs based on metabolic regulation, as well as for optimizing combination therapy strategies. Full article

Background/Objectives: Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options restricted to benznidazole and nifurtimox, both associated with significant toxicity and reduced efficacy during chronic infection. Seeking novel, safe, and sustainable chemotherapeutic candidates, two new saturated cardanol-derived phospholipid analogs—LDT10 and LDT119—were rationally designed based on the molecular scaffold of miltefosine and biosourced from cashew nut shell liquid (CNSL). This study aimed to evaluate the pharmacokinetic properties of these compounds in silico and assess their antiparasitic activity, cytotoxicity, and morphological and ultrastructural effects on all developmental forms of T. cruzi in vitro. Materials and Methods: In silico ADMET predictions (SwissADME, pkCSM) were performed to determine bioavailability, pharmacokinetic behavior, CYP inhibition, mutagenicity, and hepatotoxicity. Antiproliferative activity was evaluated in epimastigotes, trypomastigotes, and intracellular amastigotes using dose–response assays and flow cytometry. Cytotoxicity was assessed in HEPG2 and HFF-1 cells using resazurin-based viability assays. Morphological and ultrastructural alterations were investigated through scanning (SEM) and transmission (TEM) electron microscopy. Reactive oxygen species (ROS) generation was quantified with H₂DCFDA after 4 h and 24 h of exposure. Results: In silico analyses indicated favorable drug-like profiles, high intestinal absorption (>89%), absence of mutagenicity or hepatotoxicity, and non-penetration of the blood–brain barrier. LDT10 was not a P-gp substrate, and LDT119 acted as a P-gp inhibitor, suggesting reduced efflux and higher intracellular retention. Both compounds inhibited epimastigote proliferation with low IC₅₀ values (LDT10: 0.81 µM; LDT119: 1.2 µM at 48 h) and reduced trypomastigote viability (LD₅₀ LDT10: 2.1 ± 2 µM; LDT119: 1.8 ± 0.8 µM). Intracellular amastigotes were highly susceptible (IC₅₀ LDT10: 0.48 µM; LDT119: 0.3 µM at 72 h), with >90% inhibition at higher concentrations. No cytotoxicity was observed in mammalian cells up to 20 µM. SEM revealed membrane wrinkling, pore-like depressions, rounded cell bodies, and multiple flagella, indicating cell division defects. TEM showed Golgi disorganization, autophagic vacuoles, mitochondrial vesiculation, and abnormal kinetoplast replication, while host cells remained structurally preserved. Both compounds induced significant ROS production in trypomastigotes after 24 h in a dose-dependent manner. Conclusions: LDT10 and LDT119 exhibited potent and selective in vitro activity against all developmental stages of T. cruzi, with low micromolar to submicromolar IC₅₀/LD₅₀ values, minimal mammalian cytotoxicity, and extensive morphological and ultrastructural damage consistent with disruption of phospholipid biosynthesis pathways. Combined with favorable in silico pharmacokinetic predictions, these CNSL-derived phospholipid analogs represent promising candidates for future Chagas disease chemotherapy and warrant further in vivo evaluation. Full article

The proteasome β5 subunit plays a central role in protein degradation and is an established therapeutic target in glioblastoma. Marizomib (MZB), a natural β5 inhibitor, has shown promising anticancer activity, yet suboptimal pharmacological properties limit its clinical translation. Using a comprehensive computational approach, this study aimed to identify and characterize novel MZB analogs with improved binding affinity, stability, and drug-like profiles. An integrative in silico study was performed, including molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, molecular dynamics (MD) simulations over 200 ns, MM/PBSA binding free energy calculations, and per-residue energy decomposition. ADMET profiling evaluated the pharmacokinetic and safety properties of MZB and top-performing analogs. Docking and pharmacophore modeling revealed strong complementarity between MZB analogs and the β5 catalytic pocket. MD simulations showed that MZBMOD-77 and MZBMOD-79 exhibited exceptional structural stability with low RMSD values (0.40–0.42 nm), persistent binding within the active site cavity, and significant disruption of hydrogen-bond networks in the active loop regions Ala19–Lys33 and Val87–Gly98. MM/PBSA analysis confirmed their superior binding free energies (−19.99 and −18.79 kcal/mol, respectively), surpassing native MZB (−6.26 kcal/mol). Per-residue decomposition highlighted strong contributions from Arg19, Ala20, Lys33, and Ala50. ADMET predictions indicated improved oral absorption, reduced toxicity, and favorable pharmacokinetics compared to native MZB. This integrative computational study identifies MZBMOD-77 and MZBMOD-79 as promising next-generation proteasome β5 inhibitors. These analogs mimic and enhance the inhibitory mechanism of native MZB, offering potential candidates for further optimization and preclinical development in glioblastoma therapy. Full article

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a central therapeutic target in Alzheimer’s disease, as it catalyzes the rate-limiting step in amyloid-β production. Verubecestat (VER), a clinical BACE1 inhibitor, failed in late-stage trials due to limited efficacy and safety concerns. This study employed an integrative computational approach to design VER derivatives with improved binding affinity, stability, and pharmacokinetic profiles. Structural similarity analysis, Molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, 200 ns molecular dynamics (MD) simulations, MM/PBSA free energy calculations, and per-residue decomposition were performed. In silico ADMET profiling assessed drug-likeness, absorption, and safety parameters. Docking and pharmacophore analyses identified derivatives with stronger complementarity in the BACE1 catalytic pocket. MD simulations revealed that VERMOD-33 and VERMOD-57 maintained low root mean square deviations (RMSDs) and stable binding orientations and induced characteristic flexibility in the flap and catalytic loops surrounding the catalytic dyad (Asp93 and Asp289), consistent with inhibitory activity. MM/PBSA confirmed the superior binding free energies of VERMOD-33 (−51.12 kcal/mol) and VERMOD-57 (−43.85 kcal/mol), both outperforming native VER (−35.33 kcal/mol). Per-residue decomposition highlighted Asp93, Asp289, and adjacent flap residues as major energetic contributors. ADMET predictions indicated improved oral absorption, BBB penetration, and no mutagenicity or toxicity alerts. Rationally designed VER derivatives, particularly VERMOD-33 and VERMOD-57, displayed enhanced binding energetics, stable inhibitory dynamics, and favorable pharmacokinetic properties compared with native VER. These findings provide a computational framework for rescuing VER and support further synthesis and experimental validation of next-generation BACE1 inhibitors for Alzheimer’s disease. Full article

A novel series of Schiff bases (3a–3k), incorporating tranexamic acid (TXA) and phenol-derived aldehydes via imine linkers, was synthesized and structurally characterized. The antimicrobial activity of the compounds was evaluated against a range of clinically and environmentally relevant bacterial and fungal strains. Among them, derivatives 3i and 3k, bearing bromine and chlorine substituents on the phenol ring, exhibited the most potent antimicrobial effects, particularly against Penicillium italicum and Proteus mirabilis (MIC as low as 0.014 mg/mL). To elucidate the underlying mechanism of action, in silico molecular docking studies were conducted, revealing strong binding affinities of 3i and 3k toward fungal sterol 14α-demethylase (CYP51B), with predicted binding energies surpassing those of the reference antifungal ketoconazole. Additionally, UV-Vis and fluorescence spectroscopy assays demonstrated good stability of compound 3k in PBS and its effective binding to human serum albumin (HSA), respectively. ADMET and ProTox-II predictions further supported the drug-likeness, low toxicity (Class 4), and favorable pharmacokinetic profile of compound 3k. Collectively, these findings highlight TXA–phenol imine derivatives as promising scaffolds for the development of next-generation antimicrobial agents, particularly targeting resistant fungal pathogens. Full article

Background/Objectives: Plant-derived diuretics are attracting increasing interest due to their promising efficacy and improved safety profile compared with synthetic drugs. This study aimed to characterize the phytochemical composition of Astragalus boeticus (A. boeticus) extracts, evaluate their diuretic activity, and assess the oral safety of their main phenolic compound. Methods: Aqueous (AQE) and hydroethanolic (EtOHE) extracts were analyzed using LC–MS/MS, while in silico toxicity prediction of trans-resveratrol was performed using ProTox-II and ADMETlab 2.0. Diuretic activity was evaluated in male Wistar rats (n = 24) divided into four groups: control (distilled water, 10 mL/kg), furosemide (10 mg/kg), AQE (300 mg/kg), and EtOHE (300 mg/kg). Urine and plasma samples were collected after 15 days to determine electrolyte concentrations, creatinine level, creatinine clearance, and hepatic enzyme profile. Results: LC–MS/MS profiling identified fourteen phenolic compounds, with trans-resveratrol (270 µg/g in AQE) being the most abundant, followed by cyanidin-3-O-glucoside and gentisic acid. In silico assessments revealed no hepatotoxic, mutagenic, or neurotoxic effects of trans-resveratrol. Both extracts significantly enhanced urinary output, chloride excretion, and creatinine clearance, while maintaining stable renal and hepatic biochemical parameters, indicating potent diuretic activity without toxicity. Conclusions: A. boeticus extracts demonstrate strong diuretic potential associated with a favorable safety profile, likely linked to their phenolic composition dominated by trans-resveratrol. These findings support the use of A. boeticus as a natural and safe diuretic source. Further investigation is recommended to elucidate its pharmacological mechanisms and therapeutic relevance. Full article

The emergence of multidrug-resistant Staphylococcus aureus underscores the urgent need for novel therapeutic agents targeting essential bacterial pathways. The lipoteichoic acid synthase (LtaS) is crucial for the synthesis of lipoteichoic acid in the cell wall of Gram-positive bacteria and represents a promising and vulnerable target for antimicrobial drug development. This study employed a comprehensive computational pipeline to identify potent inhibitors of the LtaS enzyme. A library of natural compounds was retrieved from the COCONUT database and screened against the crystal structure of the extracellular domain of LtaS (eLtaS) (PDB ID: 2W5R, obtained from the Protein Data Bank) through a multi-stage molecular docking strategy. This process started with High-Throughput Virtual Screening (HTVS), followed by Standard Precision (SP) docking, and culminated in Extra Precision (XP) docking to refine the selection of hits. The top-ranking compounds from XP docking were subsequently subjected to MM-GBSA binding free energy calculations for further filtration. The stability and dynamic behavior of the resulting candidate complexes were then evaluated using 100 ns molecular dynamics (MD) simulations, which confirmed the structural integrity and binding stability of the ligands. Density Functional Theory calculations revealed that screened ligands exhibit improved electronic stabilization and charge-transfer characteristics compared to a reference compound, suggesting enhanced reactivity and stability relevant for hit identification. Finally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling was conducted to assess the drug-likeness and pharmacokinetic safety of the lead compounds. These findings support them as promising orally active leads for further optimization. Our integrated approach shortlisted eight initial hits (A–H) that showed interesting scaffold diversity and finally identified two compounds, herein referred to as Compound A and Compound B, which demonstrated stable binding, favorable free energy, and an acceptable Absorption, Distribution, Metabolism, and Excretion, and Toxicity (ADMET) profile. These candidates emerge as promising starting points for developing novel anti-staphylococcal agents targeting the LtaS enzyme that cand be further proved by experimental validation. Full article

Hendra virus (HeV) is a highly pathogenic zoonotic paramyxovirus that poses a serious threat to human and equine health, yet no approved antivirals or vaccines currently exist. RNA-dependent RNA polymerase (RdRp) of Hendra virus represents a critical and attractive target for antiviral drug development, given its essential role in both viral genome replication and mRNA transcription. Due to the lack of a human homolog, it is more druggable and less likely to cause host toxicity. Its sequence conservation among related paramyxoviruses further highlights its potential for the development of broad-spectrum inhibitors. This study offers the first comprehensive computational analysis of the Hendra virus RdRp, potentially promising FDA-approved drugs as possible inhibitors. A homology model of RdRp was generated in the absence of experimental three-dimensional (3D) structure, followed by virtual screening and molecular dynamics (MD) simulations to evaluate the drug binding and stability. Based on the highest energy, four FDA-approved drugs selected were menadiol diphosphate (−49.88 kcal/mol), masoprocol (−39.69 kcal/mol), pamidronic acid (−34.29 kcal/mol), and dinoprostone (−46.90 kcal/mol). Furthermore, these compounds exhibited significant interactions with the catalytic GDNE motif. With strong conformational stability and pharmacokinetic profile, masoprocol and menadiol diphosphate showed the most stable and energetically favorable interactions within the RdRp active site. These findings suggest their potential as repurposed therapeutic candidates against Hendra virus infection and they provide a structural basis for the development of broad-spectrum paramyxovirus inhibitors, justifying additional experimental confirmation. Full article

Breast cancer is the most common cancer and the most important cause of cancer-related death in females worldwide. Antibody–drug conjugates (ADCs) represent a novel class of targeted therapies that combine the precision of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. This review highlights recent mechanistic, technological, and clinical developments of ADCs in breast cancer, including next-generation ADCs beyond those that target HER2 (human epidermal growth factor receptor 2). Authors performed a systematic literature study for ADCs and their structural features, including their components (antibody, linker, and payload) and their therapeutic efficacy. A frame of preclinical research findings and clinical evidence integration of HER2-targeted therapy outcomes in HER2-positive, HER2-low, and triple-negative breast cancer (TNBC) subtypes were presented. Clinical studies of antibody–drug conjugates such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have demonstrated significant improvements in progression-free survival and overall survival across diverse breast cancer patient populations. ADCs offer unique advantages in breast cancer therapy by combining the precision of targeted antibodies with the potency of chemotherapy drugs. This allows them to selectively kill cancer cells, overcome resistance, reduce toxicity to healthy tissues, and expand treatment options for difficult subtypes like HER2-low and triple-negative breast cancer. Unlike previous reviews focusing on HER2-targeted ADCs, herein we review exciting ADCs targeting HER3 HER3 (human epidermal growth factor receptor 3) and Nectin-4, as well as the implications of bispecific and immune-stimulatory ADCs in the clinic. Additionally, it features mechanism-based innovations and novel trial data that revolutionize ADC applications in the HER2-low as well as the triple-negative breast cancer subtypes. The advent of ADC is changing precision oncology in breast cancer. With a new design and indications evolving, they are an attractive avenue for bypassing resistance and reducing toxicity and ultimately improving patient outcomes in the molecular subtypes. The present review summarizes recent advancements in antibody–drug conjugates (ADCs) and emerging targeted therapeutic strategies for breast cancer. It covers mechanistic insights, linker–payload innovations, receptor-based targeting approaches, clinical trial progress, and next-generation modalities that extend beyond HER2-directed ADCs. Current challenges, safety profiles, and future opportunities in engineering more selective and effective ADC platforms are also discussed. Full article

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder requiring safer and more effective therapeutic alternatives. This study investigates a novel fucoxanthin derivative isolated from the marine brown alga Chnoospora minima using a comprehensive in silico approach. Molecular docking revealed that the derivative exhibited higher binding affinities toward α-amylase (–9.4 kcal/mol) and α-glucosidase (–8.0 kcal/mol) compared to the reference drug acarbose (–8.5 and –7.4 kcal/mol, respectively). Pharmacokinetic analysis predicted good intestinal absorption and P-gp inhibition (0.894) and moderate plasma clearance (7.864 mL/min/kg), while toxicity predictions classified it in toxicity class 3, with no respiratory or ocular toxicity. Drug-likeness evaluation showed only one Lipinski and one Veber rule violation, common for natural products. Molecular dynamics simulations conducted for 100 ns using NAMD 3.0 confirmed stable protein–ligand complexes with average RMSD values of ~1.3 Å and ~1.8 Å for α-amylase and α-glucosidase, respectively, and consistent hydrogen bonding profiles. Structural analysis identified a substitution of the allene bond with an unsaturated ketone at the C8′ position as a key contributor to enhanced enzyme interaction. The findings suggest that this fucoxanthin derivative is a promising natural candidate for T2DM therapy and warrants further investigation through lab experiments (in vitro and in vivo). Full article

Pelvic recurrence following radiotherapy for cervical cancer presents a major therapeutic challenge with historically poor prognosis and limited options. This review comprehensively examines the evolving landscape of management strategies for this condition, encompassing both local and systemic approaches. We discuss the roles of salvage surgery and advanced re-irradiation techniques, including stereotactic body radiotherapy and image-guided brachytherapy, highlighting their potential and associated toxicities. A significant focus is placed on the revolution in systemic therapy, particularly the integration of targeted agents—such as anti-angiogenic drugs, PARP inhibitors, and tyrosine kinase inhibitors—and immunotherapy, chiefly immune checkpoint inhibitors like pembrolizumab and cemiplimab. These modalities have demonstrated substantial improvements in survival outcomes in clinical trials. The review underscores the critical shift towards personalized medicine, where treatment selection is increasingly guided by molecular profiling. Finally, we explore future directions, including combination strategies, novel immunotherapies, and emerging technologies, which collectively promise to transform the management of recurrent cervical cancer from palliative control towards the goals of durable remission and functional cure. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease. Full article