Search Results (77)

Ponatinib, a third-generation BCR::ABL1 inhibitor, has antileukemic activity but is associated with cardiovascular toxicity, for which transcriptome-level responses remain incompletely characterized. Here, we defined a ponatinib-associated transcriptomic signature and examined its mechanistic implications using two public RNA sequencing (RNA-Seq) datasets: GSE186341 (11 cancer cell lines treated with kinase inhibitors) and GSE217421 (induced pluripotent stem cell (iPSC)-derived cardiomyocytes treated with approved drugs). Principal component analysis (PCA) and k-means clustering were used to define expression-based subgroups of vehicle-treated (DMSO) controls. DESeq2, followed by fixed-effect meta-analysis, estimated subgroup-specific treatment effects and pooled effect estimates across subgroups. In GSE186341, we identified 2639 meta-analytic differentially expressed genes (meta-DEGs). Among these, 81 genes were also differentially expressed in GSE217421 after ponatinib treatment, identifying an overlapping gene set across datasets. In contrast, imatinib showed no overlap with these 81 genes under the same cross-dataset analysis framework. Cardiotoxicity-relevant functions were represented by directionally consistent genes linked to cardiac repolarization-associated ion handling (KCNN3), insulin-responsive metabolic regulation (FOXO1, HK2), cyclic adenosine monophosphate (cAMP)-responsive stress signaling (RAPGEF3), and mitochondrial homeostasis and redox regulation (MCL1, GCH1). Collectively, these results define a ponatinib-associated transcriptomic signature and nominate cross-dataset transcript-level candidates for subsequent mechanistic and experimental validation in ponatinib-associated cardiotoxicity. Full article

Background: Ponatinib (PON), an effective tyrosine kinase inhibitor for leukemias harboring the T315I mutation, is limited by severe cardiotoxicity, including myocardial infarction and heart failure. Here, we investigated the therapeutic potential of Bone Morphogenetic Protein-7 (BMP-7), an anti-inflammatory growth factor, in a murine model of PON-induced cardiotoxicity. Methods: C57BL/6J mice were distributed into experimental groups receiving PON (25 mg/kg cumulative dose) either alone or with BMP-7 (600 μg/kg cumulative dose), along with a corresponding control group. Cardiac analyses included molecular and histological assessments. Results: PON administration induced a marked increase in monocyte infiltration and M1 macrophage polarization. These inflammatory events led to the upregulation of the pyroptotic cascade, leading to activation of the TGF-β1/SMAD2/3 signaling axis. In contrast, BMP-7 significantly attenuated these pathological responses by suppressing inflammation-induced pyroptosis and the TGF-β1/SMAD2/3 signaling axis. Conclusions: These findings identify inflammation-induced pyroptosis as a central driver of the pathological changes in PON-induced cardiotoxicity. Notably, our work highlights BMP-7’s capacity to inhibit these disease-related alterations. Collectively, these results expand on the current knowledge of the mechanistic framework of PON-induced cardiotoxicity, while also emphasizing BMP-7 as a promising therapeutic candidate with potential translational relevance. Full article

Chronic myeloid leukaemia (CML) is driven by the t(9;22) forming the BCR::ABL1 fusion gene, leading to the development of hyper-myeloid proliferation. This led to development of tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, and Ponatinib. However, resistance or intolerance to ATP-competitive TKIs remains a challenge for some patients. asciminib (ABL001), a novel TKI, targets the myristoyl pocket of ABL1 instead of the ATP-binding site, reducing resistance to mutations. As asciminib is linked to thrombocytopenia, its effects on platelet activation, endothelial function, and inflammation must be studied to assess its potential to promote thrombosis. The main objective of this study is to determine the potential of asciminib as a monotherapy in inducing pathological responses to platelets and endothelium over time within the vasculature. This study assessed the effects of TKIs including asciminib on platelets and thrombotic biomarkers. Washed platelets were used to measure granule secretion, thrombus formation, surface expression of glycoproteins, apoptosis, and viability. Plasma from chronically Asciminib-treated CML patients was analysed using sandwich ELISA for inflammatory and platelet–endothelial biomarkers, and thrombin generation assays were performed to study coagulation. This approach combined in vitro and ex vivo methods to explore the impact of asciminib on platelet function and thrombotic potential. The study shows that acute treatment with asciminib does not promote platelet activation or thrombus formation. Instead, it exhibits an inhibitory effect on thrombus formation in vitro and is associated with reduced thrombo-inflammatory biomarkers ex vivo in chronically treated CML patients. Asciminib was associated with increased thrombin generation over time, suggesting an effect on secondary haemostasis. Asciminib does not appear to induce a prothrombotic or proinflammatory state under the conditions studied, which may be advantageous for CML patients. However, the observed increase in thrombin generation over time suggests a potential effect on secondary haemostasis that warrants further investigation in controlled studies. 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

Background: The tyrosine kinase inhibitors (TKIs) asciminib, bosutinib, dasatinib, imatinib, nilotinib, and ponatinib have been approved for chronic myelogenous leukemia (CML) therapy. However, pharmacovigilance reports associated with these drugs are neither consistent nor homogenous, with reports of pulmonary toxicity, which could limit their utilization. To better clarify TKIs’ pulmonary risk, we used the European database EudraVigilance to conduct a study on adverse events suspected to be caused by the TKIs asciminib, bosutinib, dasatinib, imatinib, nilotinib, and ponatinib when used for CML therapy. Methods: Suspected adverse reactions to TKIs in the EudraVigilance database (2020–2024) coming from European countries and the United Kingdom were analyzed and compared through a disproportionality analysis. Results: The most frequent alerts concerned the respiratory disorders “pleural effusion” (PE) and “pulmonary arterial hypertension” (PAH) in relation to dasatinib and bosutinib use. Among the TKIs, the prescription of dasatinib is associated with a higher occurrence of PE and PAH, while the prescription of bosutinib induces PE at a minor frequency that nonetheless carries a significant risk for PAH, occurring more often in women. Conclusions: The results indicate that respiratory disorders induced by the TKIs dasatinib and bosutinib need to be diagnosed in a timely manner, and suggest that caution should be taken when prescribing these TKIs to patients affected by CML and pulmonary comorbidities. Full article

Background/Objectives: Ponatinib (PON) is a potent anticancer drug widely used to treat chronic myeloid leukemia (CML). Although many cancer survivors benefit from such therapies, managing drug-induced side effects, especially cardiotoxicity, remains a major challenge. Despite its prevalence, the exact mechanisms underlying PON-induced cardiotoxicity have not been thoroughly investigated. Additionally, the potential of Bone Morphogenetic Protein 7 (BMP-7) to alleviate these cardiotoxic effects has yet to be explored. Methods: To address these essential questions, we conducted a study using C57BL/6 mice. Mice were treated with PON (25 mg/kg cumulative dosage) or a combination of PON and BMP-7 (600 μg/kg), alongside a suitable control group. Heart function was assessed by echocardiography. Different techniques were performed to evaluate the apoptotic pathway. Histological staining was performed to investigate structural changes. Results: PON treatment increased apoptotic cell death (increased expression of BAX and caspase-3) in the heart through the PTEN/Akt signaling pathway. Further, PON treatment led to increased cardiac hypertrophy, adverse remodeling, and reduced cardiac function. Importantly, BMP-7 markedly reduced PON-induced apoptosis (increased Bcl2 expression) and its downstream effects. Conclusions: These results suggest that BMP-7 might inhibit PON-induced cardiotoxicity. Furthermore, our findings pave the way for future translational studies with BMP-7, which can demonstrate the therapeutic potential of BMP-7 in a clinical setting. Full article

Considering the relevance of hydrogen bonds and other intermolecular interactions in regulating the activity of the tyrosine kinase class of enzymes, an in-depth electronic structure study of these forces in the context of the BCR-ABL protein was performed through full optimizations using the ONIOM method. Rebastinib and ponatinib were docked to the target enzyme using AutoDock Vina to provide starting-point geometries, which were then optimized through ONIOM calculations. This study evaluated Frontier Molecular Orbitals (FMOs) and Bond-Critical Points (BCPs) located in the sites of interactions formed with accessible residues, such as Glu286, Met318, and Asp381. Ponatinib’s ONIOM-optimized structure was shown to not only form and preserve prominent interactions, which were shown to be significantly stronger than those formed by rebastinib, but also to be associated with a significant increase in the HOMO (Highest Occupied Molecular Orbital)−LUMO (Lowest Unoccupied Molecular Orbital) gap, indicating its potential to hinder catalytic activity by providing higher chemical stability when compared to rebastinib. Full article

Oral tongue squamous cell carcinoma (OTSCC) is a common type of oral cancer influenced by genetic, epigenetic, and environmental factors like exposure to environmental toxins. These environmental toxins can decrease the effectiveness of established chemotherapy drugs, such as Irinotecan, used in OTSCC treatment. Bioinformatics, drug discovery, and machine learning techniques were employed to investigate the impact of Irinotecan on OTSCC patients by identifying targets and signaling pathways, including those that positively influence protein phosphorylation, protein tyrosine kinase activity, the PI3K-Akt (Phosphatidylinositol 3-kinase- Protein Kinase B) signaling system, cancer pathways, focal adhesion, and the HIF-1 (Hypoxia-Inducible Factor 1) signaling pathway. Later, the protein–protein interactions (PPIs) network, along with twelve cytoHubba approaches to finding the most interacting molecule, was employed to find the important proteins BCL2 and EGFR. Drugs related to BCL2 and EGFR were extracted from the DGIdb database for further molecular docking. Molecular docking revealed that Docetaxel, Paclitaxel, Imatinib, Ponatinib, Ibrutinib, Sorafenib, and Etoposide showed more binding affinity than Irinotecan (i.e., −9.8, −9.6). Of these, Paclitaxel (−10.3, −11.4) and Imatinib (−9.9, −10.4) are common in targeting BCL2 and EGFR. Using these identified candidate genes and pathways, we may be able to uncover new therapeutic targets for the treatment of OTSCC. Furthermore, molecular dynamics (MD) simulations were performed for selected ligand–receptor complexes, revealing stable binding interactions and favorable energetic profiles that supported the docking results and strengthened the reliability of the proposed drug repurposing strategy. Full article

Electric fields are emerging as powerful tools to actively regulate biomolecular interactions at biointerfaces. In this study, we investigated how varying electric field strengths (0–100 mV/mm) influence the interfacial interaction between human serum albumin (HSA) and six tyrosine kinase inhibitors (TKIs): imatinib, bosutinib, dasatinib, nilotinib, ponatinib, and radotinib. Using atomic force microscopy (AFM), we quantified changes in adhesion force, specific (F_i) and non-specific (F₀) force, friction behavior, and protein morphology. Increasing field strength led to significant reductions in adhesion force (22–47%), F_i (27–44%), F₀ (38–53%), friction force (38–67%) and constant-load friction force (43–54%), along with decreased protein average surface height and roughness, indicating electric field-induced molecular compaction and interface smoothing. Notably, more hydrophobic TKIs showed greater responsiveness. These findings highlight the potential of electric fields to modulate protein–drug interactions in a controllable manner, offering a new strategy for the development of electrically tunable drug delivery systems and smart biomedical interfaces. Full article

The BCR-ABL1 fusion protein is a critical therapeutic target in Chronic Myeloid Leukemia (CML). Current monotherapy approaches involve types of inhibitors that can be categorized into ATP competitive inhibitors and allosteric inhibitors. However, resistance mutations in the tyrosine kinase domain of BCR-ABL1 have limited the effectiveness of these drugs. Research indicates that dual inhibition of BCR-ABL1 by combining these two types of inhibitors effectively addresses the issue of drug resistance as there are no overlapping resistance mechanisms. However, the underlying reasons for the observed synergistic effects have not yet been thoroughly elucidated. In this study, we employed molecular dynamics simulation to observe the synergistic interactions of BCR-ABL1 by the allosteric inhibitor asciminib and ATP competitive inhibitors nilotinib and ponatinib. Our study reveals that when asciminib binds to BCR-ABL1, nilotinib and ponatinib exhibit more substantial binding stability compared to monotherapy. At the atomic level, we have elucidated the reasons for the enhanced binding affinity of nilotinib and ponatinib when using a co-inhibition therapy. Our study reveals the allosteric communication pathway between asciminib and ponatinib, providing more detailed insights into the effectiveness of combination therapy. These findings provide valuable insights into combination therapies, aiding in the rational use of medications and guiding the design of novel inhibitors. Full article

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by activating mutations in KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors (TKIs), especially imatinib, has significantly transformed GIST treatment. However, the emergence of both primary and secondary resistance to imatinib presents ongoing therapeutic challenges. This review comprehensively explores the mechanisms underlying imatinib resistance and evaluates subsequent TKI therapies. Sunitinib, regorafenib, and ripretinib are currently approved as standard second-, third-, and fourth-line therapies, each demonstrating efficacy against distinct mutational profiles. Avapritinib, notably effective against PDGFRA D842V mutations, represents a milestone for previously untreatable subgroups. Several alternative agents—such as nilotinib, masitinib, sorafenib, dovitinib, pazopanib, and ponatinib—have shown varying degrees of success in refractory cases or specific genotypes. Investigational compounds, including crenolanib, bezuclastinib, famitinib, motesanib, midostaurin, IDRX-42, and olverembatinib, are under development to address resistant or wild-type GISTs. Despite progress, long-term efficacy remains limited due to evolving resistance. Future strategies include precision medicine approaches such as ctDNA-guided therapy, rational drug combinations, and novel drug delivery systems to optimize bioavailability and reduce toxicity. Ongoing research will be crucial for refining treatment sequencing and expanding therapeutic options, especially for rare GIST subtypes. Full article

Liver cancer is one of the most common malignancies and the second leading cause of cancer-related deaths worldwide, particularly in developing countries, where it poses a significant financial burden. Early detection and timely treatment remain challenging due to the complex mechanisms underlying the initiation and progression of liver cancer. This study aims to uncover key genomic features, analyze their functional roles, and propose potential therapeutic drugs identified through molecular docking, utilizing single-cell RNA sequencing (scRNA-seq) data from liver cancer studies. We applied two advanced hybrid methods known for their robust identification of differentially expressed genes (DEGs) regardless of sample size, along with four top-performing individual methods. These approaches were used to analyze four scRNA-seq datasets, leading to the identification of essential DEGs. Through a protein−protein-interaction (PPI) network, we identified 25 hub-of-hub genes (hHubGs) and 20 additional hHubGs from two naturally occurring gene clusters, ultimately validating a total of 36 hHubGs. Functional, pathway, and survival analyses revealed that these hHubGs are strongly linked to liver cancer. Based on molecular docking and binding-affinity scores with 36 receptor proteins, we proposed 10 potential therapeutic drugs, which we selected from a pool of 300 cancer meta-drugs. The choice of these drugs was further validated using 14 top-ranked published receptor proteins from a set of 42. The proposed candidates include Adozelesin, Tivozanib, NVP-BHG712, Nilotinib, Entrectinib, Irinotecan, Ponatinib, and YM201636. This study provides critical insights into the genomic landscape of liver cancer and identifies promising therapeutic candidates, serving as a valuable resource for advancing liver cancer research and treatment strategies. Full article

Blinatumomab, a bispecific T-cell engager (BiTE), has shown substantial efficacy in treating both relapsed/refractory (R/R) Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). With its targeted mechanism of action, favorable safety profile, and ability to induce deep molecular remissions, blinatumomab is increasingly incorporated into frontline treatment regimens for B-ALL. Recently, the Food and Drug Administration (FDA) has approved its use in the frontline setting for Ph-negative ALL. In Ph-negative ALL, combining blinatumomab with intensive chemotherapy has resulted in superior measurable residual disease (MRD) clearance and improved long-term outcomes. In Ph-positive ALL, combination therapies involving tyrosine kinase inhibitors (TKIs), particularly ponatinib and blinatumomab, are challenging the traditional approach of allogeneic hematopoietic stem cell transplantation (allo-SCT). This review explores the current evidence supporting the frontline use of blinatumomab in newly diagnosed adults with B-ALL, its impact on treatment paradigms, and potential future directions, including novel combination therapies and the role of emerging immunotherapeutic approaches. Full article

Background: Chronic myeloid leukemia (CML) relates to the abnormal presence of the Philadelphia chromosome, which originates the production of the BCR-ABL1 fusion protein and therefore leads to neoplastic transformation and unregulated cell growth. The advent of tyrosine kinase inhibitors (TKIs) has resulted in tremendous improvements in CML scenarios; however, there are practical difficulties, especially considering the late stages of the disease. This review examines recently developed strategies that are intended to increase the efficiency of treatment by overcoming TKI resistance. Methods: We performed a literature review of such databases as PubMed, Scopus, Web of Science, and Embase for the last ten years. The following keywords were used in the studies: ‘CML’, ‘TKI resistance’, ‘novel therapies’, ‘immunotherapy’, ‘targeted agents’, and ‘combination therapies’. Only those studies were included that were clinical trials and preclinical across-the-board developmental programs that attempt to target the tumor at multiple levels and not just focus on basic first-line TKIs. Results: In CML patients who do not respond to TKIs, novel therapeutics encompass ponatinib, asciminib, CAR-T immunotherapy, and BCL-2 and mTOR inhibition in conjunction with TKI therapy. This addresses both BCR-ABL1-dependent and independent resistance mechanisms, increasing the chance of achieving deeper molecular response and reduced toxicity. Nonetheless, they exhibit diverse characteristics regarding efficacy, safety, cost, and quality of life effects. Discussion: Nonetheless, numerous challenges remain regarding the understanding of the mechanisms of resistance, the long-term efficacy of novel medicines, and the ideal combinations to attain optimal outcomes. Areas of future research include the search for other patterns of molecular resistance, tailoring specific treatments to patients, and incorporating AI to improve diagnosis and monitoring. Conclusion: The introduction of novel therapeutic techniques into clinical practice needs a collaborative approach and persistent dynamism to new findings from research. Our analysis indicates that the challenges posed by resistant CML disease are complex and require further improvements in therapeutic and clinical protocol development. Full article

In a scenario characterized by continuous improvement in outcomes, Philadelphia chromosome-positive (Ph+) ALL, once considered a biologically defined subtype with one of the poorest prognoses, now includes patients achieving long-term survival even without allogeneic stem cell transplantation. First-line therapy is increasingly adopting a chemo-free approach, combining tyrosine kinase inhibitors (TKIs) with immunotherapy—specifically blinatumomab—which has resulted in high rates of complete molecular responses and improved survival outcomes. Within this paradigm shift, the allocation to transplantation is becoming increasingly selective and genomically oriented, focusing on patients with particularly unfavorable prognostic and predictive factors. For patients undergoing transplantation, maintenance therapy with TKIs has emerged as one of the most important strategies to reduce the risk of relapse. However, there remains considerable uncertainty regarding which patients benefit most from this approach, the optimal TKI agents, dosing strategies, and the duration of maintenance therapy. In this review, we aim to consolidate the available evidence on this topic, analyzing it in the context of the most recent clinical experiences. Full article