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Frontiers in Immunology 2024The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an...
INTRODUCTION
The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works.
MATERIALS AND METHODS
We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their V617F variant allele frequency ( = 24 in total).
RESULTS
The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively).
DISCUSSION
Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.
Topics: Nitriles; Humans; Pyrazoles; Pyrimidines; Myeloproliferative Disorders; Janus Kinase 2; Neoplastic Stem Cells; Models, Theoretical; Protein Kinase Inhibitors
PubMed: 38846951
DOI: 10.3389/fimmu.2024.1384509 -
Frontiers in Pharmacology 2024Despite continuous efforts to develop safer and efficient medications, malaria remains a major threat posing great challenges for new drug discovery. The emerging drug...
Despite continuous efforts to develop safer and efficient medications, malaria remains a major threat posing great challenges for new drug discovery. The emerging drug resistance, increased toxicities, and impoverished pharmacokinetic profiles exhibited by conventional drugs have hindered the search for new entities. Plasmepsins, a group of specific, aspartic acid protease enzymes, are involved in many key aspects of parasite biology, and this makes them interesting targets for antimalarial chemotherapy. Among different isoforms, PlmIX serves as an unexplored antimalarial drug target that plays a crucial role along with PlmV and X in the parasite's survival by digesting hemoglobin in the host's erythrocytes. In this study, fragment-based virtual screening was performed by modeling the three-dimensional structure of PlmIX and predicting its ligand-binding pocket by using the Sitemap tool. Screening identified the fragments with the XP docking score ≤ -3 kcal/mol from the OTAVA General Fragment Library (≈16,397 fragments), and the selected fragments were chosen for ligand breeding. The resulting ligands (≈69,858 ligands) were subsequently subjected to filtering based on the QikProp properties along with carcinogenicity testing performed using CarcinoPred-EL and then docked in the SP (≈14,078 ligands) as well as XP mode (≈3,104 ligands), and compared with that of control ligands 49C and I0L. The top-ranked ligands were taken further for the calculation of the free energy of binding using Prime MM-GBSA. Overall, a total of six complexes were taken further for MD simulation studies performed at 100 ns to attain a better understanding of the binding mechanisms, and compounds and were found to be the most efficient ones . The analysis of compound revealed that the carbonyl group present in position 1 on the isoindoline moiety (Arg554) was responsible for inhibitory activity against PlmIX. However, the analysis of compound revealed that the amide linkage sandwiched between the phenyl ring and isoquinoline moiety (Lys555 and Ser226) as well as carbonyl oxygen of the carbamoyl group present at position 2 of the pyrazole ring (Gln222) were responsible for PlmIX inhibitory activity, owing to their crucial interactions with key amino acid residues.
PubMed: 38846093
DOI: 10.3389/fphar.2024.1387629 -
Acta Crystallographica. Section E,... May 2024The title compound, tetra-ethyl-ammonium...
The title compound, tetra-ethyl-ammonium tri-azido-tri-μ-sulfido-[μ-(tri-methyl-sil-yl)aza-nediido][tris-(3,5-di-methyl-pyrazol-1-yl)hydro-borato]triiron(+2.33)molybdenum(IV), (CHN)[FeMoS(CHBN)(CHNSi)(N)] or (EtN)[(Tp*)MoFeS(μ-NSiMe)(N)] [Tp* = tris-(3,5-di-methyl-pyrazol-1-yl)hydro-bor-ate(1-)], crystallizes as needle-like black crystals in space group . In this cluster, the Mo site is in a distorted octa-hedral coordination model, coordinating three N atoms on the Tp* ligand and three μ-bridging S atoms in the core. The Fe sites are in a distorted tetra-hedral coordination model, coordinating two μ-bridging S atoms, one μ-bridging N atom from MeSiN, and another N atom on the terminal azide ligand. This type of heterometallic and heteroleptic single cubane cluster represents a typical example within the Mo-Fe-S cluster family, which may be a good reference for understanding the structure and function of the nitro-genase FeMo cofactor. The residual electron density of disordered solvent mol-ecules in the void space could not be reasonably modeled, thus the SQUEEZE [Spek (2015). . C, 9-18] function was applied. The solvent contribution is not included in the reported mol-ecular weight and density.
PubMed: 38845704
DOI: 10.1107/S2056989024004833 -
Journal of the American Heart... Jun 2024We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular...
Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability.
BACKGROUND
We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear.
METHODS AND RESULTS
The effects of ibrutinib on cardiac electrical activity and Ca dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, <0.002) and shorter action potential durations during pacing at various frequencies (<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (<0.05). Significant changes in myocardial Ca transients included lower amplitude alternans ratios (<0.05), longer times-to-peak (<0.05), and greater spontaneous intracellular Ca elevations (<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside ameliorated abnormalities in action potential and Ca dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, <0.05) in hearts from ibrutinib-treated rats.
CONCLUSIONS
VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.
Topics: Animals; Adenine; Piperidines; Action Potentials; Pyrimidines; AMP-Activated Protein Kinases; Pyrazoles; Male; Arrhythmias, Cardiac; Protein Kinase Inhibitors; Heart Rate; Isolated Heart Preparation; Calcium; Rats; Disease Models, Animal; Rats, Sprague-Dawley; Myocytes, Cardiac; Calcium Signaling; Time Factors
PubMed: 38842296
DOI: 10.1161/JAHA.123.032357 -
Journal of Medical Economics 2024
Re: Johansson E, Giovannitti M, Mezzetti M, et al. Cost-effectiveness analysis of baricitinib versus dupilumab for moderate to severe atopic dermatitis: an Italian healthcare system perspective. J Med Econ. 2023;26(1):1155-1166.
Topics: Dermatitis, Atopic; Humans; Antibodies, Monoclonal, Humanized; Purines; Cost-Benefit Analysis; Pyrazoles; Azetidines; Sulfonamides; Italy; Severity of Illness Index; Cost-Effectiveness Analysis
PubMed: 38842021
DOI: 10.1080/13696998.2024.2357978 -
Arthritis Research & Therapy Jun 2024A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus... (Review)
Review
BACKGROUND
A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature.
METHODS
Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted.
RESULTS
Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them.
CONCLUSIONS
This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).
Topics: Humans; Giant Cell Arteritis; Female; Janus Kinase Inhibitors; Aged; Male; Retrospective Studies; Recurrence; Treatment Outcome; Pyrimidines; Piperidines; Azetidines; Pyrazoles; Sulfonamides; Purines; Aged, 80 and over; Middle Aged; Heterocyclic Compounds, 3-Ring
PubMed: 38840219
DOI: 10.1186/s13075-024-03314-9 -
ESMO Open Jun 2024In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired...
BACKGROUND
In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.
PATIENTS AND METHODS
Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.
RESULTS
Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.
CONCLUSIONS
PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.
Topics: Humans; Female; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Aged; Adult; Antineoplastic Combined Chemotherapy Protocols; Maximum Tolerated Dose; Oxazoles; Quinazolines; Paclitaxel; Uracil; Ado-Trastuzumab Emtansine; Fulvestrant; Trastuzumab; Imidazoles; Oxazepines; Antibodies, Monoclonal, Humanized
PubMed: 38833970
DOI: 10.1016/j.esmoop.2024.103465 -
PloS One 2024Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration... (Comparative Study)
Comparative Study
PURPOSE
Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs.
METHODS
A kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs.
RESULTS
Vorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs.
CONCLUSIONS
Vorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD.
Topics: Axitinib; Humans; Sunitinib; Angiogenesis Inhibitors; Imidazoles; Pyrroles; Indoles; Human Umbilical Vein Endothelial Cells; Receptors, Vascular Endothelial Growth Factor; Indazoles; Animals; Protein Kinase Inhibitors; Receptor, TIE-2; Neovascularization, Pathologic
PubMed: 38833447
DOI: 10.1371/journal.pone.0304782 -
Platelets Dec 2024The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL...
The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.
Topics: Humans; Pyrazoles; Benzoates; Receptors, Thrombopoietin; Hydrazones; Mesenchymal Stem Cells; Hydrazines; Molecular Dynamics Simulation; Angiogenesis
PubMed: 38832545
DOI: 10.1080/09537104.2024.2359028 -
Oncotarget Jun 2024Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable... (Review)
Review
Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Protein Kinase Inhibitors; Cardiotoxicity; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Adenine; Risk Assessment; Pyrimidines; Pyrazoles; Biomarkers; Polymorphism, Single Nucleotide; KCNQ1 Potassium Channel; Tyrosine Kinase Inhibitors
PubMed: 38829647
DOI: 10.18632/oncotarget.28589