-
British Journal of Pharmacology Jun 2022RNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in transcriptional co-regulation and alternative RNA splicing. Recent studies have revealed that... (Review)
Review
RNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in transcriptional co-regulation and alternative RNA splicing. Recent studies have revealed that RBM39 is the unexpected target of aryl sulphonamides, which act as molecular glues between RBM39 and the DCAF15-associated E3 ubiquitin ligase complex leading to selective degradation of the target. Loss of RBM39 leads to aberrant splicing events and differential gene expression, thereby inhibiting cell cycle progression and causing tumour regression in a number of preclinical models. Many clinical studies have shown that aryl sulphonamides were well tolerated, but their clinical performance was limited due to an insufficient understanding of the target, RBM39 biology and a lack of predictive biomarkers. This review summarises the current knowledge of RBM39 function and discusses the therapeutic potential of this spliceosome target in cancer therapy. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.
Topics: Alternative Splicing; Humans; Neoplasms; RNA-Binding Motifs; RNA-Binding Proteins; Sulfonamides
PubMed: 33238031
DOI: 10.1111/bph.15331 -
Internal Medicine (Tokyo, Japan) Jan 2020Helicobacter pylori can infect the gastric mucosa and cause chronic inflammation, resulting in various diseases, including gastric cancer. Eradication of H. pylori in... (Review)
Review
Helicobacter pylori can infect the gastric mucosa and cause chronic inflammation, resulting in various diseases, including gastric cancer. Eradication of H. pylori in all infected subjects is recommended; however, the number of H. pylori strains with antibiotic resistance has increased, and the eradication rate has decreased. Vonoprazan, a potassium-competitive acid blocker, produces a stronger acid-inhibitory effect than proton pump inhibitors (PPIs). The H. pylori eradication rate with vonoprazan was found to be higher than that with PPIs. The H. pylori eradication rate with vonoprazan-based triple therapy (vonoprazan, amoxicillin, and clarithromycin) was approximately 90% and had an incidence of adverse events similar to that of PPIs. We review the current situation of H. pylori eradication in Japan, the first country in which vonoprazan was made available.
Topics: Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Drug Therapy, Combination; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Proton Pump Inhibitors; Pyrroles; Sulfonamides
PubMed: 31243237
DOI: 10.2169/internalmedicine.2521-18 -
Cancer Discovery Apr 2020Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance...
Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.
Topics: Aged; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 31974170
DOI: 10.1158/2159-8290.CD-19-0710 -
Bioorganic & Medicinal Chemistry Letters Mar 2022We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for...
We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity. We identified two compounds with IC values <5 µM against ex vivo Schistosoma mansoni.
Topics: Animals; Carbolines; Dose-Response Relationship, Drug; Molecular Structure; Schistosoma mansoni; Structure-Activity Relationship; Sulfonamides
PubMed: 35031451
DOI: 10.1016/j.bmcl.2022.128546 -
Stroke Oct 2022Atherosclerosis is the leading cause of cardiovascular disease worldwide, including in China. Primary prevention, through lipid-lowering, could avert development of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Atherosclerosis is the leading cause of cardiovascular disease worldwide, including in China. Primary prevention, through lipid-lowering, could avert development of atherosclerosis. Carotid intima-media thickness (CIMT) is a well-validated measure of atherosclerosis used in intervention studies as the primary outcome and alternative end point for cardiovascular disease events.
METHODS
This randomized, double-blind, placebo-controlled, multicenter, parallel-group study assessed the effects of rosuvastatin 20 mg/d compared with placebo on progression of CIMT over 104 weeks in Chinese people with subclinical atherosclerosis. The primary end point was the annualized rate of change in mean of the maximum CIMT measurements taken 7× over the study period from each of 12 carotid artery sites (near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery). Secondary end points included CIMT changes at different artery sites and lipid-parameter changes. Safety was also assessed.
RESULTS
Participants were randomized (1:1) to receive rosuvastatin (n=272) or placebo (n=271). Baseline characteristics were well balanced between groups. The change in mean of the maximum CIMT of the 12 carotid sites was 0.0038 mm/y (95% CI, -0.0023-0.0100) for the rosuvastatin group versus 0.0142 mm/y (95% CI, 0.0080-0.0204) for the placebo group, with a difference of -0.0103 mm/y (95% CI, -0.0191 to -0.0016; =0.020). For the CIMT secondary end points, the results were generally consistent with the primary end point. There were clinically relevant improvements in lipid parameters with rosuvastatin. We observed an adverse-event profile consistent with the known safety profile of rosuvastatin.
CONCLUSIONS
Rosuvastatin 20 mg/d significantly reduced the progression of CIMT over 2 years in Chinese adults with subclinical atherosclerosis and was well tolerated.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT02546323.
Topics: Adult; Atherosclerosis; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Disease Progression; Fluorobenzenes; Humans; Lipids; Pyrimidines; Rosuvastatin Calcium; Sulfonamides
PubMed: 36017704
DOI: 10.1161/STROKEAHA.120.031877 -
Drugs Dec 2021Abrocitinib (Cibinqo) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis... (Review)
Review
Abrocitinib (Cibinqo) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis (AD). In September 2021, abrocitinib was approved in the UK and Japan for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older who are candidates for systemic therapy. Abrocitinib has also received a positive CHMP opinion in the EU for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Regulatory applications for the drug have also been submitted for review to several other countries, including the USA and Australia. This article summarizes the milestones in the development of abrocitinib leading to this first approval for the treatment of moderate-to-severe AD.
Topics: Clinical Trials as Topic; Dermatitis, Atopic; Drug Approval; Drug Interactions; Humans; Janus Kinase Inhibitors; Pyrimidines; Sulfonamides
PubMed: 34807428
DOI: 10.1007/s40265-021-01638-3 -
British Journal of Haematology Oct 2021Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib... (Randomized Controlled Trial)
Randomized Controlled Trial
Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400-mg daily was based on results of an updated analysis of the pivotal phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first-line fedratinib in patients with myelofibrosis.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Case-Control Studies; Follow-Up Studies; Humans; Janus Kinase 2; Janus Kinase Inhibitors; Middle Aged; Placebos; Primary Myelofibrosis; Pyrrolidines; Safety; Spleen; Splenomegaly; Sulfonamides
PubMed: 34331348
DOI: 10.1111/bjh.17727 -
Nature Communications Sep 2023The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and...
The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies.
Topics: Humans; Sulfonamides; ATP-Binding Cassette Transporters; Antineoplastic Agents; Leukemia, Myeloid, Acute; Glutathione; Proto-Oncogene Proteins c-bcl-2
PubMed: 37726279
DOI: 10.1038/s41467-023-41229-2 -
Hematological Oncology Apr 2022This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between...
This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 35043428
DOI: 10.1002/hon.2964 -
Chemical & Pharmaceutical Bulletin 2021Natural products are an important source of medicinal seeds. The discovery of novel biosynthetic enzymes from nature is important for their use as biocatalysts for the... (Review)
Review
Natural products are an important source of medicinal seeds. The discovery of novel biosynthetic enzymes from nature is important for their use as biocatalysts for the enzymatic synthesis of useful natural products. In addition, genetics and structural biology developments have enabled the engineering of enzymes for the production of unnatural analogs of bioactive natural products. In this review, I describe the recent research on these two topics, the exploitation of a novel secondary metabolite enzyme involved in the biosynthesis of the sulfonamide natural product antibiotic SB-203208, and the production of unnatural bioactive depsipeptides by reconstruction of the modular enzyme assembly lines in the microbial host.
Topics: Anti-Bacterial Agents; Biological Products; Depsipeptides; Indenes; Molecular Conformation; Sulfonamides
PubMed: 33952851
DOI: 10.1248/cpb.c21-00032