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Blood Apr 2024Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those...
Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Agammaglobulinaemia Tyrosine Kinase; Genomics; Mutation; Myeloid Differentiation Factor 88; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, CXCR4; Waldenstrom Macroglobulinemia
PubMed: 38211337
DOI: 10.1182/blood.2022017235 -
The New England Journal of Medicine Jul 2023
Topics: Humans; Acetamides; Antineoplastic Agents; Carcinoma, Squamous Cell; Pyrazoles; Skin Neoplasms; Protein Kinase Inhibitors
PubMed: 37437151
DOI: 10.1056/NEJMc2304157 -
The Medical Letter on Drugs and... May 2024
Topics: Humans; Quinoxalines; Pyrazoles; Antineoplastic Agents; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Protein Kinase Inhibitors; Urologic Neoplasms; Treatment Outcome
PubMed: 38696316
DOI: 10.58347/tml.2024.1702g -
International Journal of Dermatology Jun 2024
Review
Topics: Humans; Janus Kinase Inhibitors; Alopecia; Cicatrix; Pyrazoles; Pyrimidines; Nitriles; Sulfonamides; Treatment Outcome; Azetidines; Heterocyclic Compounds, 3-Ring; Piperidines; Purines
PubMed: 38571280
DOI: 10.1111/ijd.17153 -
Future Medicinal Chemistry Sep 2023There has been an increasing trend in the design of novel pyrazole derivatives for desired biological applications. For a cost-effective strategy, scientists have... (Review)
Review
There has been an increasing trend in the design of novel pyrazole derivatives for desired biological applications. For a cost-effective strategy, scientists have implemented various computational drug design tools to go hand in hand with experiments for the design and discovery of potentially effective pyrazole-based therapeutics. This review highlights the milestones of pyrazole-containing inhibitors and the use of molecular modeling techniques in conjunction with experimental studies to provide a view of the binding mechanism of these compounds. The review focuses on the established targets that play a key role in cancer therapy, including proteins involved in tubulin polymerization, carbonic anhydrase and tyrosine kinase. Overall, using both experimental and computational methods in drug design represents a promising approach to cancer therapy.
Topics: Humans; Molecular Structure; Antineoplastic Agents; Models, Molecular; Pyrazoles; Neoplasms; Structure-Activity Relationship; Molecular Docking Simulation
PubMed: 37772542
DOI: 10.4155/fmc-2023-0142 -
The Lancet. Haematology Mar 2024Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who...
BACKGROUND
Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG.
METHODS
SOAR was a multicentre, single-arm phase 2 trial investigating eltrombopag and cyclosporin in adult (≥18 years) patients with severe aplastic anaemia who were treatment-naive and had an Eastern Cooperative Oncology Group performance status of less than 2. Participants were recruited from 20 hospitals in ten countries. Eltrombopag was initiated at 150 mg (100 mg in patients of Asian ethnicity) and cyclosporin at 10 mg/kg per day (adjusted to a trough of 200-400 μg/L) orally from day 1 to 6 months. The primary outcome was an overall haematological response rate by 6 months in the intention-to-treat population. This is the final report of the primary analysis period. The trial was registered with ClinicalTrials.gov, NCT02998645, and has been completed.
FINDINGS
54 patients were enrolled between May 11, 2017, and March 23, 2020. 34 (63%) patients were male and 20 (37%) were female. 22 (41%) were Asian, 22 (41%) were White, one (2%) was Native American or Alaska Native, one (2%) was Black or African American, and eight (15%) were other race or ethnicity. 35 patients (65%) completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI 33-60). The most reported adverse events were increased serum bilirubin (in 22 patients [41%]), nausea (16 [30%]), increased alanine aminotransferase concentration (12 [22%]), and diarrhoea (12 [22%]). Eight patients died on-treatment, but no deaths were considered related to the treatment.
INTERPRETATION
Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated.
FUNDING
Novartis Pharmaceuticals.
Topics: Adult; Female; Humans; Male; Anemia, Aplastic; Antilymphocyte Serum; Benzoates; Cyclosporine; Hydrazines; Pyrazoles; Drug Therapy, Combination
PubMed: 38335978
DOI: 10.1016/S2352-3026(23)00395-2 -
Journal of Drugs in Dermatology : JDD Mar 2024Topical ruxolitinib, a potent Janus kinase (JAK) inhibitor, has shown significant efficacy in treating inflammatory skin conditions. While its use has already been...
Topical ruxolitinib, a potent Janus kinase (JAK) inhibitor, has shown significant efficacy in treating inflammatory skin conditions. While its use has already been established in atopic dermatitis and vitiligo, recent reports suggest its potential efficacy in treating other dermatoses. Specifically, topical ruxolitinib may be an effective treatment option for refractory dermatological conditions that are inflammation-driven with dysregulated activity of cytokines implicated in the JAK/STAT pathway. In this case series, we present four novel clinical applications of topical ruxolitinib in treatment-resistant dermatological conditions. These cases include pediatric lichen sclerosus et atrophicus, morphea, perioral dermatitis, and notalgia paresthetica. All four patients reported noticeable symptomatic improvement and a significant improvement in the condition of their skin lesions. Our results suggest that ruxolitinib cream can successfully manage these conditions and may serve as supporting evidence for its formal evaluation. J Drugs Dermatol. 2024;23(3): doi:10.36849/JDD.7696.
Topics: Humans; Child; Janus Kinases; STAT Transcription Factors; Signal Transduction; Cytokines; Janus Kinase Inhibitors; Nitriles; Pyrazoles; Pyrimidines
PubMed: 38443119
DOI: 10.36849/jdd.7696 -
Hematological Oncology Jul 2024Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR)... (Review)
Review
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Pyrazoles; Pyrimidines; Protein Kinase Inhibitors; Piperidines; Lymphoma, B-Cell; Tyrosine Kinase Inhibitors
PubMed: 38847437
DOI: 10.1002/hon.3294 -
Science Bulletin May 2024Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage...
Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal-organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.
Topics: Metal-Organic Frameworks; Gallbladder Neoplasms; Humans; Tumor Suppressor Protein p53; Animals; Cell Line, Tumor; Protein-Tyrosine Kinases; Mice; Antineoplastic Agents; Pyrazoles; Cell Cycle Proteins; Synthetic Lethal Mutations; Reactive Oxygen Species; Xenograft Model Antitumor Assays; Mutation; Mice, Nude; DNA Damage; Female; Pyrimidinones
PubMed: 38519399
DOI: 10.1016/j.scib.2024.02.039 -
The New England Journal of Medicine Apr 2024
Topics: Humans; Pyrazoles; Pyridines; Urinary Tract Physiological Phenomena; Kidney; Lung Neoplasms; Protein Kinase Inhibitors
PubMed: 38598583
DOI: 10.1056/NEJMc2400216