Explore the vast range of titles available.

Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC). In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3–23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1–16·6) in the dacomitinib group and 9·2 months (9·1–11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47–0·74; p<0·0001). The most common grade 3–4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population. SFJ Pharmaceuticals Group and Pfizer.

After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.

A placebo-controlled study of idelalisib in patients with relapsed chronic lymphocytic leukemia who were receiving rituximab was stopped early because of significant improvement in rates of response, progression-free survival, and overall survival with idelalisib. Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among adults. Standard treatments include combinations of purine analogues, alkylating agents, and monoclonal antibodies. In younger patients without major coexisting illnesses, these regimens can provide high response rates of durable length but have substantial toxic effects. As a result, these treatments often have unacceptable side effects in older patients and those with coexisting illnesses. 1 Patients with relapsed CLL often have limited options because of the development of resistance to, or persisting toxic effects of, previous therapies. This is particularly true for elderly patients and those with coexisting illnesses. 2 For these patients, . . .

Idelalisib, which inhibits PI3K isoform delta, produced antitumor responses in nearly 60% of pretreated patients with indolent non-Hodgkin's lymphomas. Responses lasted a median of 11 months. Grade 3 or higher toxic effects were seen in 13 to 27% of patients. Indolent non-Hodgkin's lymphomas constitute approximately one third of all cases of non-Hodgkin's lymphoma and include follicular lymphoma, small lymphocytic lymphoma, marginal-zone lymphoma, and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia. 1 – 3 It was estimated that approximately 20,000 people in the United States were diagnosed with indolent non-Hodgkin's lymphoma in 2012 and that approximately 7000 died of this disease. 4 , 5 The mainstay of treatment for indolent non-Hodgkin's lymphoma is an anti-CD20 antibody (primarily rituximab) in combination with chemotherapy consisting of alkylating agents, anthracyclines, antimitotic agents, or purine analogues. Although the current treatments for indolent non-Hodgkin's lymphomas are initially effective in inducing . . .

Quinazolinones, essential quinazoline derivatives, exhibit diverse biological activities with applications in pharmaceuticals and insecticides. Some derivatives have already been developed as commercial drugs. Given the rising cancer incidence, there is a critical need for new anticancer agents, and quinazolinones show promising potential in this domain. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, the structure–activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives, to help in the development of new quinazoline and quinazolinone derivatives.

Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6–29·6) for patients in the dacomitinib group and 24·4 months (11·5–38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08–7·49] for dacomitinib vs 6·31 months [5·32–7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83–1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91–3·32] vs 1·38 months [0·99–1·74], respectively; HR 0·66 [95% CI 0·55–0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67–1·44) and EGFR wild-type tumours (0·93, 0·71–1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05–4·22) and patients with KRAS wild-type tumours (0·79, 0·61–1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3–4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Canadian Cancer Society Research Institute and Pfizer.

Quinazolines are nitrogen-containing heterocycles that consist of a benzene ring fused with a pyrimidine ring. Quinazolinones, oxidized quinazolines, are promising compounds with a wide range of biological activities. In the pharmaceutical field, quinazolinones are the building blocks of more than 150 naturally occurring alkaloids isolated from different plants, microorganisms, and animals. Scientists give a continuous interest in this moiety due to their stability and relatively easy methods for preparation. Their lipophilicity is another reason for this interest as it helps quinazolinones in penetration through the blood–brain barrier which makes them suitable for targeting different central nervous system diseases. Various modifications to the substitutions around the quinazolinone system changed their biological activity significantly due to changes in their physicochemical properties. Structure–activity relationship (SAR) studies of quinazolinone revealed that positions 2, 6, and 8 of the ring systems are significant for different pharmacological activities. In addition, it has been suggested that the addition of different heterocyclic moieties at position 3 could increase activity. In this review, we will highlight the chemical properties of quinazolinones, including their chemical reactions and different methods for their preparation. Moreover, we will try to modify some of the old SAR studies according to their updated biological activities in the last twelve years.

Bacterial signaling systems are prime drug targets for combating the global health threat of antibiotic resistant bacterial infections including those caused by Staphylococcus aureus. S. aureus is the primary cause of acute bacterial skin and soft tissue infections (SSTIs) and the quorum sensing operon agr is causally associated with these. Whether efficacious chemical inhibitors of agr signaling can be developed that promote host defense against SSTIs while sparing the normal microbiota of the skin is unknown. In a high throughput screen, we identified a small molecule inhibitor (SMI), savirin (S. aureus virulence inhibitor) that disrupted agr-mediated quorum sensing in this pathogen but not in the important skin commensal Staphylococcus epidermidis. Mechanistic studies employing electrophoretic mobility shift assays and a novel AgrA activation reporter strain revealed the transcriptional regulator AgrA as the target of inhibition within the pathogen, preventing virulence gene upregulation. Consistent with its minimal impact on exponential phase growth, including skin microbiota members, savirin did not provoke stress responses or membrane dysfunction induced by conventional antibiotics as determined by transcriptional profiling and membrane potential and integrity studies. Importantly, savirin was efficacious in two murine skin infection models, abating tissue injury and selectively promoting clearance of agr+ but not Δagr bacteria when administered at the time of infection or delayed until maximal abscess development. The mechanism of enhanced host defense involved in part enhanced intracellular killing of agr+ but not Δagr in macrophages and by low pH. Notably, resistance or tolerance to savirin inhibition of agr was not observed after multiple passages either in vivo or in vitro where under the same conditions resistance to growth inhibition was induced after passage with conventional antibiotics. Therefore, chemical inhibitors can selectively target AgrA in S. aureus to promote host defense while sparing agr signaling in S. epidermidis and limiting resistance development.

A series of novel phenylamino quinazolinone derivatives were designed and synthesized as potential tyrosinase inhibitors. Among these compounds, 9r emerged as the most potent derivative, exhibiting IC 50 values of 17.02 ± 1.66 µM, compared to kojic acid as the positive control with an IC 50 value of 27.56 ± 1.27 µM. Antioxidant assessment of 9r compounds showed 24.67% inhibition at 100 µM. Molecular docking studies of these derivatives were conducted, revealing their proper fitting within the enzyme’s active site. Additionally, density functional theory analysis was performed on the potent derivatives, indicating their stability and reactivity. Notably, the highest values of the energy gap were observed in 9r and 9s derivatives, underscoring their potential efficacy. Further kinetic studies of compound 9r , identified as the most potent derivative, demonstrated a competitive mode of inhibition with a K i value of 14.87 µM. Molecular dynamics simulations of the 9r -tyrosinase complex revealed stability over time, with a reduction in critical residual fluctuation during the simulation. Overall, these findings contribute to a deeper understanding of the potential therapeutic value of these derivatives as tyrosinase inhibitors.

Inhibiting Cyclin-dependent kinase 2 (CDK2) has been established as a therapeutic strategy for the treatment of many cancers. Accordingly, this study aimed at developing a new set of quinazolinone-based derivatives as CDK2 inhibitors. The new compounds were evaluated for their anticancer activity against sixty tumour cell lines. Compounds 5c and 8a showed excellent growth inhibition against the melanoma cell line MDA-MB-435 with GI% of 94.53 and 94.15, respectively. Cell cycle analysis showed that compound 5c led to cell cycle cessation at S phase and G2/M phase revealing that CDK2 could be the plausible biological target. Thus, the most cytotoxic candidates 5c and 8a were evaluated in vitro for their CDK2 inhibitory activity and were able to display significant inhibitory action. The molecular docking study confirmed the obtained results. ADME study predicted that 5c had appropriate drug-likeness properties. These findings highlight a rationale for further development and optimisation of novel CDK2 inhibitors.