Search Results (70)

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

Introduction: Tyrosine kinase inhibitors (TKIs) serve as the backbone in the management of chronic myelogenous leukemia and Philadelphia-positive Acute lymphoblastic Leukemia (Ph+ve ALL). With the growing use of TKIs, there has been an increase in adverse events related to these agents. Hereby, we present elderly women with Ph+ve ALL who developed recurrent pleural effusion, which was managed by switching the TKI and highlighting pleural effusion due to a third-generation TKI Bosutinib, adding to the minimal available literature. Case Description: Our patient is a 79-year-old female with Ph+ve ALL diagnosed in 2015 and started on treatment. She is also on TKI maintenance initially with Imatinib later shifted to second-generation TKIs. She started developing worsening dyspnea related to pulmonary toxicity related to TKI in the form of pleural effusion. Pleural effusion was initially managed with diuretics, later requiring thoracocentesis. Because of persistent pleural effusion, she was changed to multiple TKIs and finally started on Bosutinib. She even developed progressive pleural effusion while on Bosutinib which is managed by thoracocentesis. Conclusions: Through this case report, we would like to highlight refractory recurrent pleural effusion caused by bosutinib adding to the minimal available literature. In addition, we highlight the various treatment options in patients having cross-intolerance to various TKIs, especially pulmonary toxicity, and ponatinib might be a suitable option in such cases. Full article

Blood flow is an important physiological endpoint to measure cardiovascular performance in animals. Because of their innate transparent bodies, zebrafish is an excellent animal model for assessing in vivo cardiovascular performance. Previously, various helpful methods for measuring blood flow in zebrafish larvae were discovered and developed. However, an optimized method to measure blood flow in adult zebrafish has not been reported. In this paper, the tail fin region was selected as target for blood flow measurements using the Trackmate method, provided by ImageJ platform. Based on power statistic calculations, the aortic vessel at the tail base was selected, and other parameters, such as ambient temperature, were investigated for method standardization, in order to minimize experimental variation. The method was also validated using fenpropathrin and ponatinib, which showed some cardiac alterations in a previous zebrafish study. We also checked the versatility of this method by following the same setup in black tetra and medaka and found that this method performed well. However, our results show that heavy pigmentation, like that found in tiger barb, and overlapping vessels, like those in parrot fish, make it hard for this method to perform well. Overall, an optimized protocol was used for the first time to measure blood flow velocity in adult wild-type zebrafish without the aid of transgenic lines or fluorescent dye. Full article

Background/Objectives: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Methods: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. Results: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3–8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Conclusions: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target–drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML. Full article

The advent of tyrosine kinase inhibitors (TKIs) has changed the natural history of chronic myeloid leukemia (CML), and the transformation from the chronic phase to the blast phase (BP) is currently an uncommon situation. However, it is one of the major remaining challenges in the management of this disease, as it is associated with dismal outcomes. We report the case of a 63-year-old woman with a history of CML with poor response to imatinib who progressed to myeloid BP-CML, driven by the acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1. The patient received intensive chemotherapy and dasatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, she suffered an early relapse after allo-HSCT with the acquisition of the T315I mutation in ABL1. Ponatinib and azacitidine were started as salvage treatment, allowing for the achievement of complete remission with deep molecular response after five cycles. Advances in the knowledge of disease biology and clonal evolution are crucial for optimal treatment selection, which ultimately translates into better patient outcomes. Full article

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1^T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Full article

Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions. Full article

The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5–6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2–63) after Allo-SCT (p = 0.01). The median starting dose of PONA was 30 mg/day (range 15–45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7–118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2–100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank p = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE. Full article