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Expert Review of Clinical Pharmacology Aug 2018In August 2017, the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous... (Review)
Review
In August 2017, the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2. Areas covered: We review the studies leading to enasidenib's approval, as well as common side effects and safety issues experienced during the clinical trials. There is a focus on the diagnosis and treatment of these side effects including differentiation syndrome. Expert commentary: We are experiencing a revolution in the understanding of the mechanism of AML. A majority of the effort has been concentrated on targeting gene mutations or pathway activations with precision therapeutics. Enasidenib is beneficial in a patient population that previously had limited treatment options. However, given the fact that enasidenib is a highly specific inhibitor of an early stable mutation, it is questionable whether a strategy of targeting a single mutation or pathway in relapsed AML will allow for better than the 20% complete remission (CR) rate observed with this therapy. The proper role for single mutation targeting in AML needs to be carefully considered.
Topics: Adult; Aminopyridines; Antineoplastic Agents; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Mutation; Triazines
PubMed: 29770715
DOI: 10.1080/17512433.2018.1477585 -
Expert Opinion on Investigational Drugs Mar 2015Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has... (Review)
Review
INTRODUCTION
Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types.
AREAS COVERED
This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials.
EXPERT OPINION
Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.
Topics: Aminopyridines; Animals; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Molecular Targeted Therapy; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction
PubMed: 25645727
DOI: 10.1517/13543784.2015.1008132 -
Journal of Thrombosis and Haemostasis :... Apr 2023Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors are an essential treatment modality for hormone receptor-positive breast cancer. As the rates of breast cancer continue... (Review)
Review
Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors are an essential treatment modality for hormone receptor-positive breast cancer. As the rates of breast cancer continue to rise globally and the indications for CDK 4/6 inhibitors now extend beyond metastatic disease, more patients than ever are receiving these agents. Thrombosis is an emerging clinical concern with this class of agents, particularly venous thromboembolism. Although venous thromboembolism initially emerged as an adverse effect of interest in early trials, more recent studies have demonstrated even higher incidences of thrombosis in real-world clinical practice. In this review, we summarize the evidence to date that has informed the thrombosis risk for these agents both in clinical trials and real-world studies. We review data describing the venous and arterial thromboembolic risks in clinical trials of CDK 4/6 inhibitors as well as the now rather extensive real-world evidence available, including a comparison of risk for each of the 3 agents approved for use in breast cancer: palcociclib, ribociclib, and abemaciclib. As the role of prophylactic anticoagulation continues to remain unknown in women receiving CDK 4/6 inhibitors, future efforts directed at carefully investigating the risks and benefits of thromboprophylaxis may lead to improved outcomes in these patients.
Topics: Humans; Female; Pyridines; Cyclin-Dependent Kinase 4; Venous Thromboembolism; Anticoagulants; Protein Kinase Inhibitors; Aminopyridines; Breast Neoplasms
PubMed: 36696184
DOI: 10.1016/j.jtha.2022.12.001 -
Molecules (Basel, Switzerland) Mar 2022A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The...
A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5-3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2--substituted aminopyridines from various secondary -alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.
Topics: Amides; Aminopyridines; Catalysis; Hydrolysis; Indicators and Reagents
PubMed: 35335206
DOI: 10.3390/molecules27061833 -
Journal of Medicinal Chemistry Sep 2015Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion,... (Review)
Review
Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
Topics: Aminopyridines; Animals; Arthritis, Rheumatoid; Asthma; Dermatitis, Atopic; Drug Partial Agonism; Histamine Agonists; Histamine Antagonists; Humans; Hypersensitivity; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship
PubMed: 25993395
DOI: 10.1021/acs.jmedchem.5b00516 -
Pulmonary Pharmacology & Therapeutics Feb 2021The recent pandemic of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an extraordinary challenge to identify... (Review)
Review
The recent pandemic of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an extraordinary challenge to identify effective drugs for prevention and treatment. The pathogenesis implicate acute respiratory disorder (ARD) which is attributed to significantly triggered "cytokine storm" and compromised immune system. This article summarizes the likely benefits of roflumilast, a Phosphodiesterase-4 (PDE-4) inhibitor as a comprehensive support COVID-19 pathogenesis. Roflumilast, a well-known anti-inflammatory and immunomodulatory drug, is protective against respiratory models of chemical and smoke induced lung damage. There is significant data which demonstrate the protective effect of PDE-4 inhibitor in respiratory viral models and is likely to be beneficial in combating COVID-19 pathogenesis. Roflumilast is effective in patients with severe COPD by reducing the rate of exacerbations with the improvement of the lung function, which might further be beneficial for better clinical outcomes in COVID-19 patients. However, further clinical trials are warranted to examine this conjecture.
Topics: Aminopyridines; Anti-Inflammatory Agents; Benzamides; COVID-19; Cyclopropanes; Cytokines; Inflammation Mediators; Pandemics; Phosphodiesterase 4 Inhibitors; COVID-19 Drug Treatment
PubMed: 33259924
DOI: 10.1016/j.pupt.2020.101978 -
Chemistry, An Asian Journal May 2022We developed a facile, efficient method for synthesizing highly substituted 2-aminopyridines from unstable vinyl carbodiimides generated in situ in a one-pot...
We developed a facile, efficient method for synthesizing highly substituted 2-aminopyridines from unstable vinyl carbodiimides generated in situ in a one-pot transformation. A series of novel highly substituted 3-functionalized 2-aminopyridines were produced in good yields. Reaction mechanism studies, which included control experiments and density-functional theory (DFT) calculations, demonstrated that Rh and potassium carbonate played key roles in the cyclization step.
Topics: Aminopyridines; Azides; Cyclization; Ketones
PubMed: 35277925
DOI: 10.1002/asia.202200083 -
Targeted Oncology Mar 2023Abemaciclib [Verzenio (USA) or Verzenios (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for... (Review)
Review
Abemaciclib [Verzenio (USA) or Verzenios (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Antineoplastic Combined Chemotherapy Protocols; Aminopyridines
PubMed: 36826463
DOI: 10.1007/s11523-023-00952-y -
Anti-cancer Agents in Medicinal... 2017Epigenetic modifications play central roles in cellular differentiation and their deregulations really contribute to tumor development. Histone deacetylase (HDAC)... (Review)
Review
Epigenetic modifications play central roles in cellular differentiation and their deregulations really contribute to tumor development. Histone deacetylase (HDAC) enzymes can exert their functions in the epigenetic regulation of gene expression related to oncogenesis via deacetylating the lysine residues of histones in the chromatin and various non-histone proteins. A majority of HDAC inhibitors (HDACIs) have been in different stages of preclinical and clinical trials with potent anticancer activity recently. Among these agents, chidamide tested as either monotherapeutic agent or in combination regimens for numerous hematological and solid malignancies has shown promising potential as an orally active subtype-selective HDACI. Herein we will highlight the progress of clinical trials of chidamide and rationally analyze those results from both preclinical and clinical studies about chidamide as an epigenetic modulator in cancer therapy.
Topics: Administration, Oral; Aminopyridines; Antineoplastic Agents; Benzamides; Clinical Trials as Topic; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors; Humans; Neoplasms
PubMed: 27592546
DOI: 10.2174/1871520616666160901150427 -
Cell Chemical Biology Jun 2023Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride...
Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Most people with CF harbor a common misfolded variant (ΔF508) that can be partially rescued by therapeutic "correctors" that restore its expression. Nevertheless, many other CF variants are insensitive to correctors. Using deep mutational scanning, we quantitatively compare the effects of two correctors on the plasma membrane expression of 129 CF variants. Though structural calculations suggest corrector binding provides similar stabilization to most variants, it's those with intermediate expression and mutations near corrector binding pockets that exhibit the greatest response. Deviations in sensitivity appear to depend on the degree of variant destabilization and the timing of misassembly. Combining correctors appears to rescue more variants by doubling the binding energy and stabilizing distinct cotranslational folding transitions. These results provide an overview of rare CF variant expression and establish new tools for precision pharmacology.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis; Mutation; Cell Membrane; Aminopyridines
PubMed: 37253358
DOI: 10.1016/j.chembiol.2023.05.001