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Blood Advances May 2024First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more...
First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.
Topics: Humans; Pyrimidines; Pyrazoles; Piperidines; Male; Aged; Female; Protein Kinase Inhibitors; Middle Aged; Cardiovascular Diseases; Adenine; Agammaglobulinaemia Tyrosine Kinase; Incidence; Atrial Fibrillation; Aged, 80 and over
PubMed: 38502198
DOI: 10.1182/bloodadvances.2023011641 -
Current Medical Research and Opinion Nov 2023Zanubrutinib is a highly selective, next-generation Bruton's tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
OBJECTIVE
Zanubrutinib is a highly selective, next-generation Bruton's tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients' health-related quality-of-life (HRQoL).
METHODS
In the SEQUOIA trial, patient-reported outcomes (PROs) were assessed at baseline and every 12 weeks (3 cycles) using the EORTC QLQ-C30 and EQ-5D-5L. Descriptive analyses were performed on all the questionnaires' scales and a mixed model for repeated measures was performed using the key QLQ-C30 endpoints of global health status/QoL (GHS/QoL), physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting at weeks 12 and 24.
RESULTS
Compared with BR-treated patients, those in the zanubrutinib arm experienced greater improvements in HRQoL outcomes at both weeks 12 and 24. By week 24, mean change differences (95% confidence interval) between the arms were significant for GHS/QoL (4.9 [0.9, 9.0]), physical functioning (3.8 [0.8, 6.7]), diarrhea (-6.2 [-10.0, -2.5]), fatigue (-4.5 [-8.9, -0.1]), and nausea/vomiting (-4.5 [-8.9, -0.1]); role functioning (4.8 [-0.2, 9.7]) was marginally better in the zanubrutinib arm and there were no differences in pain symptoms (-0.4 [-4.3, 5.1]) between the arms.
CONCLUSIONS
During the first 24 weeks of treatment, zanubrutinib was associated with better HRQoL outcomes in patients with treatment-naive CLL/SLL without del(17p) compared to BR.
TRIAL REGISTRATION
The SEQUOIA trial is registered on clinicaltrials.gov as SEQUOIA trial (NCT03336333).
Topics: Humans; Quality of Life; Rituximab; Bendamustine Hydrochloride; Pyrimidines; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Female; Pyrazoles; Aged; Middle Aged; Piperidines; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Adult
PubMed: 37752878
DOI: 10.1080/03007995.2023.2262381 -
Future Medicinal Chemistry Aug 2023Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent... (Review)
Review
Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent need for the development of novel potent chemical entities. Azoles, particularly pyrazole, could interact with different biological targets and exhibit diverse biological properties including anticancer activity. Many clinically used anticancer agents own an azole moiety, demonstrating that azoles are privileged and pivotal templates in the discovery of novel anticancer chemotherapeutics. The present article is an attempt to highlight the recent advances in pyrazole-azole hybrids with anticancer potential and discuss the structure-activity relationships, covering articles published from 2018 to present, to facilitate the rational design of more effective anticancer candidates.
Topics: Humans; Azoles; Structure-Activity Relationship; Antineoplastic Agents; Neoplasms; Pyrazoles
PubMed: 37610862
DOI: 10.4155/fmc-2023-0138 -
Bioorganic Chemistry Oct 2023Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically...
Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-β stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-β/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1β (IL-1β) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.
Topics: Mice; Animals; Receptor, Transforming Growth Factor-beta Type I; Protein Serine-Threonine Kinases; Receptors, Transforming Growth Factor beta; Mice, Inbred NOD; Fibrosis; Liver Cirrhosis; Inflammation; Transforming Growth Factor beta; Hepatitis; Pyrazoles
PubMed: 37459824
DOI: 10.1016/j.bioorg.2023.106723 -
Journal of Enzyme Inhibition and... Dec 2023Twenty-five azole compounds (-) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass...
Twenty-five azole compounds (-) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities and . exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC 15.9 μM), with activity greater than arbutin and kojic acid. Also, exhibited noteworthy free radical-scavenging activity. Furthermore, docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified - some with multiple activities - warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents.
Topics: Humans; Monophenol Monooxygenase; Antioxidants; Molecular Structure; Enzyme Inhibitors; Molecular Docking Simulation; Computer Simulation; Skin Neoplasms; Azoles; Pyrazoles
PubMed: 37184042
DOI: 10.1080/14756366.2023.2205042 -
Hematological Oncology Mar 2024Zanubrutinib has been approved for treating patients with different lymphoproliferative disorders and now represents a significant breakthrough in treating... (Review)
Review
Zanubrutinib has been approved for treating patients with different lymphoproliferative disorders and now represents a significant breakthrough in treating relapsed/refractory and previously untreated patients with chronic lymphocytic leukemia (CLL). Because few systematic studies or comparative randomized clinical trials have been conducted, optimal use of zanubrutinib in approved indications may be challenging. This article presents the results of a group discussion among an ad hoc constituted panel of experts to identify and address unmet clinical needs (UCNs) in using zanubrutinib in patients with CLL. Key UCNs were selected according to the criterion of clinical relevance using the Delphi process. Panel members reviewed the results of first-line and upstream controlled trials in which the efficacy and toxicity profile of zanubrutinib and other BTK inhibitors were investigated in patients with CLL. Based on a critical discussion of data, the panel produced recommendations for using zanubrutinib and proposals for new studies to increase the evidence for the optimal treatment of patients with CLL. The recommendations given by the panel are intended for use not only by expert centers but, above all, by less experienced hematologists as well as general practitioners.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Consensus; Pyrazoles; Pyrimidines; Protein Kinase Inhibitors; Piperidines
PubMed: 38362952
DOI: 10.1002/hon.3255 -
Blood Advances Jun 2024The efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy vs zanubrutinib in patients with treatment-naive chronic lymphocytic... (Comparative Study)
Comparative Study
The efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy vs zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma without del(17p) were compared using an unanchored matching-adjusted indirect comparison. Individual patient-level data from ELEVATE-TN (acalabrutinib plus obinutuzumab, n = 162; acalabrutinib monotherapy, n = 163) were weighted to match published aggregate baseline data from SEQUOIA cohort 1, which excluded patients with del(17p) (zanubrutinib, n = 241), using variables that were prognostic/predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory Cox regression analysis of ELEVATE-TN. After matching, INV-PFS was longer with acalabrutinib plus obinutuzumab (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.23-0.74) and comparable with acalabrutinib monotherapy (HR, 0.91; 95% CI, 0.53-1.56) vs zanubrutinib. Acalabrutinib monotherapy had significantly lower odds of any grade hypertension vs zanubrutinib (odds ratio [OR], 0.44; 95% CI, 0.20-0.99), whereas acalabrutinib plus obinutuzumab had significantly higher odds of neutropenia (OR, 2.19; 95% CI, 1.33-3.60) and arthralgia (OR, 2.33; 95% CI, 1.37-3.96) vs zanubrutinib. No other significant differences in safety were observed. In summary, acalabrutinib plus obinutuzumab had longer INV-PFS with increased odds of neutropenia and arthralgia than zanubrutinib, whereas acalabrutinib monotherapy had similar INV-PFS with lower odds of any grade hypertension. These trials were registered at www.ClinicalTrials.gov as #NCT02475681 and #NCT03336333.
Topics: Humans; Benzamides; Antibodies, Monoclonal, Humanized; Pyrazines; Female; Male; Aged; Pyrimidines; Pyrazoles; Middle Aged; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Treatment Outcome; Piperidines
PubMed: 38598745
DOI: 10.1182/bloodadvances.2023012142 -
Clinical Immunology (Orlando, Fla.) Dec 2023The benefits of IL2RA antagonists in heart transplant patients are controversial. We aimed to elucidate the effects of IL2RA antagonists and identify targets that could...
The benefits of IL2RA antagonists in heart transplant patients are controversial. We aimed to elucidate the effects of IL2RA antagonists and identify targets that could be better than IL2RA antagonists. By using single-cell RNA sequencing of immune cells at different time points in patients receiving IL2RA antagonists, we identified nineteen types of cells. We revealed higher IL2RA expression in regulatory T cells (Tregs), suggesting that IL2RA antagonists attenuated IL-2-induced Treg activation. CD4_C04_IFNGR1 and CD8_C05_IFITM2 which had more cytotoxic effects, remained elevated at later time points. IFNGR1 was upregulated in these two subtypes, but was not expressed in Treg. Ruxolitinib targeted the pathways of IFNGR1 (JAK1/2) while not affecting the pathway of IL-2-induced Tregs activation (JAK3). Ruxolitinib showed prolonged survival compared to IL2RA mAb-treated mice. Our study provided dynamic changes of immune cells after IL2RA antagonists treatment at single-cell resolution. Ruxolitinib has potential as a new immunoinduction therapy without affecting Treg.
Topics: Humans; Animals; Mice; Interleukin-2; Induction Chemotherapy; Pyrazoles; T-Lymphocytes, Regulatory; Heart Transplantation; Graft Rejection; Membrane Proteins
PubMed: 38008145
DOI: 10.1016/j.clim.2023.109851 -
Archives of Gynecology and Obstetrics Nov 2023Cystic fibrosis (CF) causes infertility and subfertility due to various factors, including altered cervical mucus, delayed puberty, and hormonal imbalances. With the...
Cystic fibrosis (CF) causes infertility and subfertility due to various factors, including altered cervical mucus, delayed puberty, and hormonal imbalances. With the introduction of the CFTR modulator therapy elexacaftor-tezacaftor-ivacaftor, we have observed an increase in unplanned pregnancies among women undergoing ETI treatment in our CF center, despite repeated recommendations for strict fertility monitoring. It appears that these pregnancies are more likely attributed to reduced attention to the possibility of conception rather than contraceptive failure. The perception of subfertility developed by women with CF over time, before the era of modulators, can influence their long-term habits and lead to the underuse of contraceptive methods. While further research is needed to fully understand the effects of ETI on fertility, healthcare providers should be attentive to the fertility concerns of women with CF, particularly those treated with modulators in adulthood.
Topics: Female; Humans; Pregnancy; Cystic Fibrosis; Infertility; Mutation; Pregnancy, Unplanned; Chloride Channel Agonists; Pyrazoles
PubMed: 37517074
DOI: 10.1007/s00404-023-07153-y -
ChemMedChem Apr 2024N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage...
N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage diversification of 3-bromopyrazoles 10 A/B and 14 A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electron-withdrawing properties of the cyano moiety in 4-position of the pyrazole ring limited the acylation of the primary amino moiety in 5-position. A large set of pyrazoles bearing diverse aryl and alkynyl substituents in 3-position was prepared and the antileishmanial and antitrypanosomal activity was recorded. The urea 38 lacking the electron withdrawing cyano moiety in 4-position and containing the large 4-benzylpiperidinoo moiety exhibited a modest antileishmanial (IC=19 μM) and antitrypanosomal activity (IC=7.9 μM)). However, its considerable toxicity against the PMM and MRC-5 cells indicates low selectivity, i. e. a small gap between the desired antiparasitic activity and undesired cytotoxicity of <2- to 4-fold.
Topics: Antiprotozoal Agents; Antiparasitic Agents; Pyrazoles
PubMed: 38289147
DOI: 10.1002/cmdc.202400028