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Current Oncology Reports Jun 2022Cyclin-dependent kinases (CDKs) are key regulators that play an important role in cell division. Palbociclib, ribociclib and abemaciclib showed significant antitumor... (Review)
Review
PURPOSE OF REVIEW
Cyclin-dependent kinases (CDKs) are key regulators that play an important role in cell division. Palbociclib, ribociclib and abemaciclib showed significant antitumor activity in several malignancies and, recently, also a myeloprotective effect for trilaciclib when added to chemotherapy. The purpose of this review is to highlight the current evidence for CDK4/6 inhibitors in neuroendocrine neoplasms (NENs).
RECENT FINDINGS
Preclinical results showed a promising antitumor activity of CDK4/6 inhibitors in neuroendocrine tumors (NETs), but so far, the very few small clinical trials did not show a strong impact on progression free survival (PFS) and objective response in NETs. Meanwhile, the CDK4/6 inhibitor trilaciclib revealed significant effects in reducing chemotherapy-induced myelosuppression in small cell lung cancer (SCLC). Up to date, CDK4/6 inhibitors are still considered investigational in NETs as antitumor agents, whereas trilaciclib can be used in the routine clinical practice in extensive stage SCLC patients for reducing myelotoxicity of standard chemotherapy.
Topics: Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Lung Neoplasms; Neuroendocrine Tumors; Protein Kinase Inhibitors; Small Cell Lung Carcinoma
PubMed: 35262877
DOI: 10.1007/s11912-022-01251-x -
Expert Review of Clinical Pharmacology Oct 2017Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic... (Review)
Review
Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use. Expert commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV (ppFEV) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care.
Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Forced Expiratory Volume; Humans; Molecular Targeted Therapy; Mutation; Quinolones
PubMed: 28891346
DOI: 10.1080/17512433.2017.1378094 -
Journal of Chromatographic Science Mar 2016In this article, retention modeling of eight aminopyridines (synthesized and characterized at the Faculty of Pharmacy) in reversed-phase high performance liquid...
In this article, retention modeling of eight aminopyridines (synthesized and characterized at the Faculty of Pharmacy) in reversed-phase high performance liquid chromatography (RP-HPLC) was performed. No data related to their retention in the RP-HPLC system were found. Knowing that, it was recognized as very important to describe their retention behavior. The influences of pH of the mobile phase and the organic modifier content on the retention factors were investigated. Two theoretical models for the dependence of retention factor of organic modifier content were tested. Then, the most reliable and accurate prediction of log k was created, testing multiple linear regression model-quantitative structure-retention relationships (MLR-QSRR) and support vector regression machine-quantitative structure-retention relationships (SVM-QSRR). Initially, 400 descriptors were calculated, but four of them (POM, log D, M-SZX/RZX and m-RPCG) were included in the models. SVM-QSRR performed significantly better than the MLR model. Apart from aminopyridines, four structurally similar substances (indapamide, gliclazide, sulfamethoxazole and furosemide) were followed in the same chromatographic system. They were used as external validation set for the QSRR model (it performed well within its applicability domain, which was defined using a bounding box approach). After having described retention of eight aminopyridines with both theoretical and QSRR models, further investigations in this field can be conducted.
Topics: Acetonitriles; Aminopyridines; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Hydrogen-Ion Concentration; Models, Statistical; Solutions; Solvents; Water
PubMed: 26590237
DOI: 10.1093/chromsci/bmv165 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2021There has been extraordinary progress in the field of targeted therapy for myeloid malignancies in the last few years, especially due to the approval of various agents... (Review)
Review
There has been extraordinary progress in the field of targeted therapy for myeloid malignancies in the last few years, especially due to the approval of various agents that can be used as monotherapy or in combination as first-line treatment or when facing a refractory or relapsed disease. Many successful trials have been conducted recently, and a consistent body of work about the efficacy of novel molecules is now available. In this review, we sought to explain how enasidenib and ivosidenib have changed the face of myeloid neoplasm treatment through isocitrate dehydrogenase inhibition and to summarize the trials results that have led to the current commercial indications for the two molecules.
Topics: Aminopyridines; Glycine; Humans; Isocitrate Dehydrogenase; Middle Aged; Pyridines; Triazines
PubMed: 34193376
DOI: 10.1016/j.clml.2021.05.004 -
Drug Design, Development and Therapy 2019Lumacaftor-ivacaftor is a combination of two small molecule therapies targeting the basic defect in cystic fibrosis (CF) at a cellular level. It is a precision medicine... (Review)
Review
Lumacaftor-ivacaftor is a combination of two small molecule therapies targeting the basic defect in cystic fibrosis (CF) at a cellular level. It is a precision medicine and its effects are specific to individuals with two copies of the p.Phe508del gene mutation. The drug combination works by restoring functioning CF transmembrane conductance regulator (CFTR) protein in cell surface membranes and was the first CFTR modulator licensed for the homozygous p.Phe508del genotype. The drug is a combination of a CFTR corrector and potentiator. Lumacaftor, the corrector, works by increasing the trafficking of CFTR proteins to the outer cell membrane. Ivacaftor, the potentiator, works by enabling the opening of what would otherwise be a dysfunctional chloride channel. In vivo lumacaftor-ivacaftor improves Phe508del-CFTR activity in airways, sweat ducts and intestine to approximately 10-20% of normal CFTR function with greater reductions in sweat chloride levels in children versus adults. Its use results in a modest improvement in lung function and a decreased rate of subsequent decline. Perhaps more importantly, those treated report increased levels of well-being and their rate of respiratory exacerbations is significantly improved. This review traces the development and use of this combination of CFTR modulators, the first licensed drug for treating the homozygous p.Phe508del CF genotype at the intracellular level by correcting the protein defect.
Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Drug Design; Drug Therapy, Combination; Humans; Quinolones
PubMed: 31409974
DOI: 10.2147/DDDT.S153719 -
Cancer Mar 2021The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT).
BACKGROUND
The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT).
METHODS
This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019.
RESULTS
One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months).
CONCLUSIONS
This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.
Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Female; Giant Cell Tumor of Tendon Sheath; Humans; Male; Middle Aged; Pyrroles; Young Adult
PubMed: 33197285
DOI: 10.1002/cncr.33312 -
Anti-cancer Drugs Aug 2023The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently...
The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently no effective treatment to improve it. In this work, we explored the effect of a synthetic compound named WXJ-103 on several aspects of TNBC biology. The human breast cancer cell lines MDA-MB-231 and MCF-7 were used in the experiments, and the cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and the cell migration and invasion abilities were detected by wound healing assay and Transwell invasion assay. Cell cycle and apoptosis experiments were analyzed by flow cytometry, and protein levels related to cyclin-dependent kinase (CDK) 4/6-cyclin D-Rb-E2F pathway were analyzed by western blotting. Then, in-vivo experiments were performed to determine the clinical significance and functional role of WXJ-103. The results show that WXJ-103 can inhibit the adhesion, proliferation, migration, and invasion of TNBC cells, and can arrest the cell cycle in G1 phase. The levels of CDK4/6-cyclin D-Rb-E2F pathway-related proteins such as CDK6 and pRb decreased in a dose-dependent manner. Therefore, the antitumor activity of WXJ-103 may depend on the inhibition of CDK4/6-cyclin D1-Rb-E2F pathway. This research shows that WXJ-103 may be a new promising antitumor drug, which can play an antitumor effect on TNBC and provide new ideas for the treatment of TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Cell Proliferation; Aminopyridines; Cyclin-Dependent Kinase 4; Purines; Cell Line, Tumor
PubMed: 36729405
DOI: 10.1097/CAD.0000000000001475 -
International Journal of Molecular... Dec 2021The big problem of antimicrobial resistance is that it requires great efforts in the design of improved drugs which can quickly reach their target of action. Studies of...
The big problem of antimicrobial resistance is that it requires great efforts in the design of improved drugs which can quickly reach their target of action. Studies of antibiotic uptake and interaction with their target it is a key factor in this important challenge. We investigated the accumulation of ozenoxacin (OZN), moxifloxacin (MOX), levofloxacin (LVX), and ciprofloxacin (CIP) into the bacterial cells of 5 species, including (SA4-149), (SEP7602), (SPY165), (SAG146), and (EF897) previously characterized.The concentration of quinolone uptake was estimated by agar disc-diffusion bioassay. Furthermore, we determined the inhibitory concentrations 50 (IC) of OZN, MOX, LVX, and CIP against type II topoisomerases from .The accumulation of OZN inside the bacterial cell was superior in comparison to MOX, LVX, and CIP in all tested species. The accumulation of OZN inside the bacterial cell was superior in comparison to MOX, LVX, and CIP in all tested species. The rapid penetration of OZN into the cell was reflected during the first minute of exposure with antibiotic values between 190 and 447 ng/mg (dry weight) of bacteria in all strains. Moreover, OZN showed the greatest inhibitory activity among the quinolones tested for both DNA gyrase and topoisomerase IV isolated from with IC50 values of 10 and 0.5 mg/L, respectively. OZN intracellular concentration was significantly higher than that of MOX, LVX and CIP. All of these features may explain the higher in vitro activity of OZN compared to the other tested quinolones.
Topics: Aminopyridines; Bacterial Proteins; Gram-Positive Bacteria; Quinolones; Topoisomerase I Inhibitors
PubMed: 34948159
DOI: 10.3390/ijms222413363 -
Bioorganic Chemistry Jan 2023Enasidenib (AG-221) is the only approved IDH2 inhibitor, clinical study found Enasidenib have some side-effects. In this work, we synthesized series of novel s-triazine...
Enasidenib (AG-221) is the only approved IDH2 inhibitor, clinical study found Enasidenib have some side-effects. In this work, we synthesized series of novel s-triazine derivatives, and the in vitro and in vivo activity of anti-AML has been studied using AM7577 model. The cell activity found Ta and Th showed excellent inhibition to AM7577. We further used the HuKemia Acute Leukemia xenograft model to investigate the in vivo efficacy of compounds Ta and Th, compared with AG-221, although Ta and Th can't reduce the 2-HG level obviously, those two compounds can prolong the survival of rats. The research can expand the structure of novel IDH2 inhibitors and provide useful information for further research of novel AML drugs.
Topics: Humans; Rats; Animals; Isocitrate Dehydrogenase; Mutation; Aminopyridines; Triazines; Leukemia, Myeloid, Acute
PubMed: 36335650
DOI: 10.1016/j.bioorg.2022.106225 -
Biomacromolecules Mar 2022HR+/HER2- metastatic breast cancer (MBC) is one of the most common and life-threatening conditions diagnosed in women. The endocrine therapy using an orally active...
HR+/HER2- metastatic breast cancer (MBC) is one of the most common and life-threatening conditions diagnosed in women. The endocrine therapy using an orally active CDK4/6 inhibitor, ribociclib (RB), is the most intriguing approach for treating HR+/HER2- MBC. However, the repeated three to six cycles of multiple dosing and non-targeted distribution of RB led to severe neutropenia; hepatobiliary, gastrointestinal, and renal toxicities, and QT interval prolongation. Here, a novel organic solvent-free HA-PVA-PVP (hyaluronic acid-polyvinyl alcohol-polyvinyl pyrrolidone) composed of a microneedle (MN) array is formulated to deliver RB, integrated with amphiphilic conjugated polymer (HA-GMS)-anchored ultradeformable transfersomes. This unique MN array efficiently crafts microchannels in the skin, allowing HA-RB-Ts to internalize into the tumor cells through lymphatic and systemic absorption and interact with CD44 both spatially and temporally with an amplification of drug release time up to 6-folds. The pharmacokinetic and tissue distribution studies portray drug concentrations within the therapeutic window as long as 48 h, facilitating thrice-a-week frequency with the lower dose, and rule out severe toxicities, with a significant reduction in 8.3-fold RB concentration in vital organs that ultimately enhances the survival rate. Thus, the novel MN system pursues a unique embeddable feature and offers an effective, self-administrable, biodegradable, and chronic treatment option for patients requiring long-term cancer treatments.
Topics: Aminopyridines; Breast Neoplasms; Drug Delivery Systems; Female; Humans; Hyaluronan Receptors; Purines
PubMed: 34978424
DOI: 10.1021/acs.biomac.1c01076