Search Results (608)

The cell division cycle machinery has been regarded as a promising therapeutic target for several decades. One of the most prominent milestones in the approach to targeting the cancer cell cycle was the development and approval of CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib. These small-molecule therapeutics have exhibited remarkable anti-cancer efficacy and have become primary choices for treating steroid receptor-positive breast cancer at multiple stages. This epoch-making success of cell-cycle-targeting drugs was followed by the development of small molecules to target other cell cycle-regulatory proteins, such as CDK2, CDK1, WEE1 kinase, Aurora kinases, and polo-like kinases, while therapeutic strategies to overcome resistance to CDK4/6 inhibitors have been pursued. In this article, we focus on heterogeneous vulnerabilities of cancers as consequences of various genetic and epigenetic alterations in the cell cycle-regulatory network, and we discuss how next-generation cell-cycle-targeting drugs currently in the developmental pipeline could exploit these heterogeneous vulnerabilities in the cancer cell cycle. We hope to provide a forward-looking perspective on directions for therapeutic cell-cycle targeting in the advent of personalized precision medicine. Full article

Background: The management of pediatric inflammatory bowel disease (PIBD) has evolved significantly over the past two decades, transitioning from corticosteroids and immunomodulators to biologic and small-molecule therapies. These advances have aimed not only to control inflammation but also to promote mucosal healing, improve growth, and enhance long-term quality of life. Objectives: This narrative review summarizes current evidence on the efficacy, safety, and clinical applications of biologic and novel small-molecule therapies in PIBD, highlighting emerging trends in personalized and precision-based management. Methods: A literature search was performed across PubMed, Embase, and the Cochrane Library, focusing on studies published within the last five years. Additional data were retrieved from key guidelines and position papers issued by ECCO–ESPGHAN, SIGENP, the FDA, and the EMA. Results: Anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab remain first-line biologics with proven efficacy in remission induction and maintenance. Newer biologics—vedolizumab, ustekinumab, risankizumab, and mirikizumab—offer alternatives for anti-TNF-refractory cases, showing encouraging short-term results and favorable safety profiles. Although many are approved only for adults with limited pediatric evidence, emerging small molecules—including Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) and sphingosine-1-phosphate (S1P) modulators (etrasimod)—provide oral, rapidly acting, and non-immunogenic treatment options for refractory disease. Furthermore, the gut microbiome is increasingly recognized as an emerging therapeutic target in PIBD, with growing evidence that host–microbiome interactions can influence both the efficacy and safety of biologics and small-molecule therapies. Conclusions: While biologics and small molecules have transformed PIBD management, challenges remain, including high treatment costs, limited pediatric trial data, and variable access worldwide. Future directions include multicenter pediatric studies, integration of pharmacogenomics, and biomarker-guided precision medicine to optimize early, individualized treatment and improve long-term outcomes. Full article

Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the BCR-ABL, among which the T315I substitution constitutes the most clinically significant barrier. Ponatinib effectively inhibits this mutant form but is limited by dose-dependent cardiovascular toxicity, prompting efforts to develop safer and more selective agents. Recent advances highlight aminopyrimidine-derived scaffolds and their evolution into thienopyrimidines, oxadiazoles, and pyrazines with improved activity against BCR-ABL^T315I. Further progress has been achieved with benzothiazole–picolinamide hybrids incorporating a urea-based pharmacophore, which benefit from strategic hinge-region substitutions and phenyl linkers that enhance potency. Parallel research into dual-mechanism inhibitors, including Aurora and p38 kinase modulators, demonstrates additional opportunities for overcoming resistance. Combination strategies, such as vorinostat with ponatinib, provide complementary therapeutic avenues. Natural-product-inspired approaches utilizing fungal metabolites provided structurally diverse scaffolds that could engage sterically constrained mutant kinases. Hybrid molecules derived from approved TKIs, including GNF-7, olverembatinib, and HG-7-85-01, exemplify rational design trends that balance efficacy with improved safety. Molecular modeling continues to deepen understanding of ligand engagement within the T315I-mutated active site, supporting the development of next-generation inhibitors. In this review, we summarized recent progress in the design, optimization, and biological evaluation of small molecules targeting the BCR-ABL^T315I mutation. Full article

Nucleoside analogs remain central to the treatment of hematologic malignancies and solid tumors, yet resistance frequently occurs, contributing to relapse and disease-related mortality. Rather than arising from a single mechanism, effective nucleoside analog activity requires successful navigation of multiple biological barriers, including cellular uptake, intracellular activation, nucleotide pool balance, genome surveillance, and mitochondrial stress responses. This review integrates recent advances describing how alterations at each of these levels contribute to resistance to nucleoside analog therapies. We further highlight emerging therapeutic strategies centered on small-molecule inhibitors that exploit these vulnerabilities to enhance the efficacy of nucleoside analogs. Together, this integrative perspective supports the need for development of small molecule inhibitors and design of combination approaches aimed at restoring apoptotic competence and improving the use of nucleoside analog-based therapies for the treatment of cancer. Full article

Focal Adhesion Kinase (FAK) is a key regulator of tumor cell migration and survival, and its persistent overexpression in aggressive cancers has motivated ongoing efforts to identify novel small-molecule inhibitors. Despite this interest, progress in discovering new potent scaffolds has been limited. In this work, we applied a multistep computational workflow followed by experimental testing to refine hit selection and reduce the false positives typically associated with docking. DrugBank and several commercial libraries were screened using Exponential Consensus Ranking (ECR) docking, and molecular dynamics simulations were used to assess pose stability and interaction persistence. A subset of predicted binders was then tested in MG-63 (bone cancer) and MDA-MB-231 (breast cancer) cells using cell viability and wound-healing assays, followed by direct autophosphorylation assays with recombinant FAK. Several repurposed compounds, including clofazimine and tafamidis, produced clear dose-dependent effects on cell migration, although their inhibitory activity in biochemical assays remained weak (${\mathrm{IC}}_{50}$ values above 100 $\mu$M), far from the potency of the reference inhibitor TAE226. Retrospective analysis of the computational workflow showed that standard MM-GBSA calculations did not correlate with these experimental outcomes. However, incorporating explicit water molecules through the NWAT-MMGBSA approach improved agreement with the biochemical data and helped to rationalize the limited affinity observed experimentally. Taken together, the results underline the relevance of explicit solvation in modeling the FAK active site and suggest that refined solvent-aware protocols may provide more reliable guidance for future screening efforts. Full article

Neuroblastoma (NB) is the most prevalent paediatric extracranial solid tumour, which remains a major therapeutic challenge, especially in cases of recurrent and disseminated disease. c-Jun N-terminal kinases (JNKs) are increasingly evidenced to play a key role in NB tumourigenesis and progression through apoptosis regulation, making selective JNK inhibitors promising candidates for use in targeted anticancer drugs in NB. Our study comprehensively investigated the acute antineoplastic potential of the selective JNK inhibitor AS601245 (JNK inhibitor V) on the human MYCN-non-amplified neuroblastoma cell line, SH-SY5Y, with particular focus on its effects on NB cell viability, proliferation, migration, apoptosis, gene and protein expression, and mitochondrial metabolism. JNK V selectively impaired NB cell survival and function, without exerting cytotoxicity toward normal human Schwann cells (HSC) and fibroblasts (BJ). Our findings highlighted a dose-dependent inhibition of proliferation (XTT assay), colony formation (clonogenic assay), and migration (wound healing assay), accompanied by increased caspase-3 activity (caspase-3 assay), pro-apoptotic genes (qRT-PCR) and protein (Western blotting) expression, and significant disruption of both oxidative phosphorylation and glycolysis (Agilent Seahorse XF Assay). These results provide new insights into the therapeutic potential of JNK inhibition as a targeted strategy for NB. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) therapies are limited by poor response, rapid resistance, and recurrence of aggressive disease. Sorafenib, a multi-tyrosine kinase inhibitor, can trigger β-catenin stabilization and activation, contributing to resistance. Overexpression of the chemokine receptor CXCR6 and its ligand CXCL16 and hyperactivation are implicated in HCC progression and β-catenin stabilization. We hypothesized that SBI-457, a small-molecule CXCR6 antagonist we developed, could disrupt CXCR6/β-catenin crosstalk and enhance sorafenib sensitivity. Methods: We tested SBI-457 alone and in combination with sorafenib in SK-Hep-1 xenograft models and a panel of human HCC cell lines. Tumor burden, β-catenin activation, and CXCR6 expression were assessed by tumor volume measurements, immunohistochemistry, Western blotting, and immunofluorescence. Soluble CXCL16 levels were quantified by ELISA, and cell death responses were evaluated using MTT assays. Results: In vivo, SBI-457 combined with sorafenib reduced normalized tumor volume by 55% compared to vehicle controls, modestly exceeding monotherapy effects, and attenuated sorafenib-induced β-catenin upregulation. In vitro, SBI-457 blocked nuclear accumulation of β-catenin and reversed sorafenib-induced increases in β-catenin levels. Enhanced cell death was observed in specific “responder” HCC cell lines (Hep-3B, SNU-398, JHH-5), which correlated with high intracellular β-catenin, secretion of soluble CXCL16, and expression of a high molecular weight form of CXCR6. In contrast, “non-responder” cell lines with conventional CXCR6 expression and low CXCL16 secretion showed no enhanced cell death response. Conclusions: CXCR6 antagonism with SBI-457 can modulate β-catenin activation and may help overcome sorafenib resistance in selected HCC models. These findings support further development of CXCR6 antagonists as single agents or combination therapies to improve treatment outcomes in HCC. Full article

Background: Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy, and overexpression of ABCB1 plays a critical role in the pathogenesis of MDR. Despite decades of research, significant clinical progress in the development of ABCB1 inhibitors has yet to be achieved. The small-molecule H89 is originally identified as an inhibitor of protein kinase A (PKA), but it also exhibits various functions unrelated to the PKA. This study investigates H89 as a novel ABCB1-inhibitor to reverse MDR in colorectal cancer (CRC). Methods: Cytotoxicity assays were performed on ABCB1-overexpressing MDR cell line HCT-8/V and parental CRC cell line HCT-8. Drug accumulation was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. The ATPase activity of ABCB1 was detected using an ATPase activity assay kit. Molecular docking utilized the ABCB1 crystal structure. Results: Both 3 μM and 10 μM H89 significantly reverses resistance to two ABCB1 substrate drugs (doxorubicin and vincristine) in HCT-8/V cells in a dose-dependent manner, with no such effect observed inHCT-8 cells. The combination of H89 and doxorubicin or vincristine resulted in a significant increase in the proportion ofHCT-8/Vcells in the sub-G1 and G2/M phases. Further mechanistic studies reveal that H89 exerts its effect by inhibiting the drug efflux function of ABCB1, thereby increasing the intracellular accumulation of the substrate drugs and reversing multidrug resistance. Furthermore, H89 did not alter the expression of ABCB1. H89 effectively inhibited the ATPase activity of ABCB1. Molecular docking simulations revealed the binding mode of H89 with ABCB1. Conclusions: The combination of H89 with ABCB1 substrate drugs significantly reverses multidrug resistance in colorectal cancer. These findings provide a strong theoretical and experimental foundation for the development of novel MDR-reversing agents targeting ABCB1. Full article

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that orchestrates multiple critical events during mitosis, including centrosome maturation, spindle assembly, kinetochore–microtubule attachment, and cytokinesis. Dysregulation and overexpression of PLK1 are frequently observed in various cancers, correlating with increased proliferation, metastatic potential, and poor prognosis, which highlights its potential as a therapeutic target. Traditional small-molecule inhibitors have predominantly focused on the ATP-binding site of the N-terminal kinase domain, effectively inducing mitotic arrest and apoptosis in tumor cells; however, these compounds often suffer from limited selectivity and off-target toxicity. The C-terminal Polo-box domain (PBD), responsible for substrate recognition and subcellular localization, has emerged as an alternative and highly selective target for inhibitor design, enabling the disruption of protein–protein interactions critical for PLK1 function. Here, we present a comprehensive review demonstrating the potential inhibition of several compounds against PLK1. This work establishes a foundation for future preclinical development of small molecule-based therapeutics against PLK1-dependent malignancies. Full article

Imatinib (IMT) is a small-molecule tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptor-β and related kinases. Beyond its established efficacy in chronic myeloid leukemia, IMT has also demonstrated therapeutic benefits in gastrointestinal stromal tumors, dermatofibrosarcoma, acute lymphoblastic leukemia, and as a second-line treatment for aggressive systemic mastocytosis or as an anti-Mycobacterium agent. From a physicochemical perspective, IMT exhibits poor aqueous solubility but high membrane permeability, classifying it as a Biopharmaceutics Classification System Class II compound. Pharmacokinetically, IMT shows variable oral absorption and a prolonged terminal half-life, resulting in dose-dependent systemic exposure. Despite relatively high oral bioavailability, its clinical use requires large doses to achieve therapeutic efficacy, underscoring the need for advanced drug delivery strategies. Nano- and microscale delivery systems offer promising approaches to enhance tumor-specific accumulation through the enhanced permeability and retention effect while mitigating resistance mechanisms. However, achieving high drug loading introduces formulation challenges, such as controlling particle size distribution, polydispersity, and scalability. Moreover, designing carriers capable of controlled release without premature leakage remains crucial for maintaining systemic bioavailability and therapeutic performance. Emerging delivery platforms—including polymeric, lipid-based, carbon-derived, and stimuli-responsive nanocarriers—have shown significant potential in overcoming these limitations. Such systems can enhance IMT’s bioavailability, improve selective tumor targeting, and minimize systemic toxicity, thereby advancing its translational potential. This review aims to highlight the different biomedical applications of IMT and off-label uses, and to discuss current advances in drug delivery to optimize its clinical efficacy and safety profile. Full article

The Aurora kinase A (Aurora-A), overexpressed in cancer cells, represents a promising anti-cancer therapeutic target due to its role in mitotic progression and chromosome instability. Aurora-A contains a recently described drug pocket within its Targeting Protein for Xklp2 (TPX2) interaction site, offering a promising target for small-molecule disruption and selective inhibition. In this study, 1281 natural products from Argentina’s database (NaturAr), encompassing chemically diverse and structurally rich metabolites, were evaluated using a machine learning model based on molecular fingerprints and variational autoencoders (VAEs) to predict inhibitory activity with high-throughput efficiency. From this initial screening, 624 compounds were classified as active type against Aurora-A, and subsequently subjected to molecular docking using FRED software (v4.3.0.3) against the Aurora-A crystal structure (PDB: 5OSD), focusing on the TPX2-binding interface. Among them, 117 compounds with various scaffolds showed better binding scores than the co-crystallized ligand, highlighting their potential to interact with the druggable target site through stable and specific molecular contacts. This workflow effectively prioritized compounds of natural origin from Argentina for the discovery of new Aurora-A kinase inhibitors, demonstrating the value of integrating AI-driven screening with structure-based modeling. These findings highlight the identification of novel scaffolds with high binding potential, offering promising starting points for the development of selective Aurora-A inhibitors. Full article

Reversine is a small-molecule Aurora kinase inhibitor known for its pro-apoptotic effects and potential to remodel chromatin architecture. Although its impact on mitotic regulation is established, its effects on telomere dynamics and nuclear organization in chronic myeloid leukemia (CML) remain unclear. This study aimed to investigate the effects of reversine on telomere architecture, genomic instability, and apoptosis in CML cell lines (K-562 and MEG-01). Reversine was applied at increasing concentrations, and cytotoxicity was assessed using caspase-3/7 activation assays. Quantitative PCR was used to measure AURKA and AURKB mRNA expressions. Three-dimensional telomere architecture was analyzed with TeloView^® v1.03 software after Q-FISH labeling to quantify telomere number, signal intensity, aggregation, nuclear volume, and a/c ratio. Reversine induced a dose- and time-dependent apoptotic response in both cell lines and significantly downregulated AURKA and AURKB expressions. Three-dimensional telomere analysis revealed a marked reduction in telomere number and aggregates, signal intensity, and nuclear volume. While reduced signal intensity may indicate telomere shortening, the concurrent decrease in aggregation and altered spatial parameters suggests telomeric reorganization rather than progressive instability. These features reflect structural nuclear remodeling and early apoptotic commitment. Differences between K-562 and MEG-01 responses underscore potential heterogeneity in telomere maintenance mechanisms. Reversine modulates genomic stability in CML cells through dual mechanisms involving Aurora kinase inhibition and telomere architecture remodeling. The integration of 3D telomere profiling highlights reversine’s potential as a therapeutic agent targeting nuclear disorganization and mitotic dysregulation in leukemia. Full article

Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target. Methods: Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines. Results: Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA. Conclusion: These findings uncover a novel TK–IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers. Full article

The urgent need to reduce the cost of new drug discovery has led us to create a new, more selective screening method using free chemoinformatics tools to restrict the high failure rates of lead compounds (>90%) during the development process because of the lack of clinical efficacy (40–50%), unmanageable toxicity (30%), and poor drug-like properties (10–15%). Our efforts focused on new molecular entities (NMEs) with reported activity as tyrosine kinase inhibitors (small molecules) as a class of great potential. The criteria for the new method are acceptable Druglikeness, desirable ADME (absorption, distribution, metabolism, and excretion), and low toxicity. After a bibliographic review, we first selected the 29 most promising compounds, always according to the literature, then collected the in silico calculated data from different platforms, and finally processed them together to conclude at 14 compounds meeting the aforementioned criteria. The novelty of the present screening method is that for the evaluation of the compounds for Druglikeness, and ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), the data of the different platforms were used as a whole, rather than the results of each platform individually. Additionally, we validated our new consensus-based method by comparing the final in silico results with the experimental values of FDA (Food and Drug Administration)-approved tyrosine kinase drugs. Using inferential statistics of 39 FDA-approved tyrosine kinase drugs obtained after applying our method, we delineated the intervals of the desired values of the physicochemical properties of future active compounds. Finally, molecular docking studies enhance the credibility of the applied method as an identification tool of Druglikeness. Full article

Resistance to conventional anti-tumor drugs is one of the significant challenges in oncology, responsible for treatment failure and patient death. Introduction of the targeted drugs (e.g., small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies) in cancer therapy significantly improved overall survival (OS) and progression-free survival (PFS) rates for selected groups of cancer patients and delayed the progression of advanced forms of human malignancies. However, the development of secondary resistance to the targeted drugs remains an unbeatable obstacle to a successful outcome in the long run, thereby making prognosis unfavorable for cancer patients with advanced, recurrent, and metastatic forms of disease. The review focuses on several mechanisms that regulate cancer resistance to conventional chemotherapies. This includes the upregulation of main types of ABC transporters (e.g., ABCB1, ABCC1, and ABCG2), which provides the efflux of chemotherapeutic agents from cancer cells. Additionally, the activation of diverse DNA damage repair (DDR) pathways, epithelial-to-mesenchymal transition (EMT), and the population of cancer stem cells (CSCs) are also discussed in detail, thereby illustrating the diverse molecular mechanisms of cancer sensitivity to chemotherapies. Recently, several TKIs, including those that were initially developed to specifically target FGFR and VEGFR pathways, have also been reported to exhibit “off-target” effects by interacting with ABC transporters and inhibiting their function. This, in turn, illustrates their potency in retaining chemotherapeutic agents within cancer cells and possessing a chemosensitizing function. Of note, FGFR and VEGFR inhibitors may behave as inhibitors or substrates of ABC transporters, depending on the expression of specific pumps and affinity for them, concentrations, and types of co-administered agents, thereby disclosing the complexity of this scenario. Additionally, the aforementioned RTKI can interfere with the other molecular mechanisms regulating tumor sensitivity to conventional chemotherapies, including the regulation of diverse DDR pathways, EMT, and the population of CSCs. Thereby, the aforementioned “off-target” functions of FGFR and VEGFR inhibitors can open novel approaches towards anti-cancer therapies and strategies aimed at counteracting cancer multidrug resistance (MDR), which is important especially as second- or third-line treatments in patients who have progressed on modern chemotherapeutic regimens. Notably, the strategy of using TKIs to potentiate the clinical efficacy of chemotherapies can extend beyond inhibitors of FGFR and VEGFR signaling pathways, thereby providing a rationale for repurposing existing TKIs as an attractive therapeutic approach to overcome cancer chemoresistance. Full article