scholarly journals Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7069
Author(s):  
Francesca Musumeci ◽  
Annarita Cianciusi ◽  
Ilaria D’Agostino ◽  
Giancarlo Grossi ◽  
Anna Carbone ◽  
...  
Keyword(s):  
Small Molecules ◽  
Pediatric Cancer ◽  
Kinase Inhibitors ◽  
Severe Disease ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Specific Mechanism ◽  
Drug Candidates ◽  
Heterocyclic Derivatives ◽  
Tumor In Childhood

In the last few years, small molecules endowed with different heterocyclic scaffolds have been developed as kinase inhibitors. Some of them are being tested at preclinical or clinical levels for the potential treatment of neuroblastoma (NB). This disease is the most common extracranial solid tumor in childhood and is responsible for 10% to 15% of pediatric cancer deaths. Despite the availability of some treatments, including the use of very toxic cytotoxic chemotherapeutic agents, high-risk (HR)-NB patients still have a poor prognosis and a survival rate below 50%. For these reasons, new pharmacological options are urgently needed. This review focuses on synthetic heterocyclic compounds published in the last five years, which showed at least some activity on this severe disease and act as kinase inhibitors. The specific mechanism of action, selectivity, and biological activity of these drug candidates are described, when established. Moreover, the most remarkable clinical trials are reported. Importantly, kinase inhibitors approved for other diseases have shown to be active and endowed with lower toxicity compared to conventional cytotoxic agents. The data collected in this article can be particularly useful for the researchers working in this area.

Probing Cellular Outcomes Using Heterobivalent Constructs

2019 ◽  
Author(s):  
Rohit Bhadoria ◽  
Kefeng Ping ◽  
Christer Lohk ◽  
Ivar Järving ◽  
Pavel Starkov
Keyword(s):  
Cell Viability ◽  
Small Molecules ◽  
Cellular Uptake ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
Intracellular Delivery ◽  
Rho Kinase Inhibitors

<div> <div> <div> <p>Conjugation techniques are central to improving intracellular delivery of bioactive small molecules. However, tracking and assessing the overall biological outcome of these constructs remains poorly understood. We addressed this issue by having developed a focused library of heterobivalent constructs based on Rho kinase inhibitors to probe various scenarios. By comparing induction of a phenotype of interest vs. cell viability vs. cellular uptake, we demonstrate that such conjugates indeed lead to divergent cellular outcomes. </p> </div> </div> </div>

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

Cytotoxic agents and radiation therapy: mechanisms of action and clinical applications

2014 ◽  
Vol 14 (1) ◽  
pp. 63-69
Author(s):  
Amanda Marrone ◽  
William T. Tran
Keyword(s):  
Cell Cycle ◽  
Radiation Therapy ◽  
Disease Free Survival ◽  
Treatment Resistance ◽  
Mechanisms Of Action ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Theoretical Frameworks ◽  
Oncological Diseases ◽  
Health Database

AbstractBackgroundThe combination of radiation therapy and chemotherapy is rooted in its ability to help achieve locoregional and systemic control, therefore increasing the overall disease-free survival of patients. Understanding the mechanistic actions of cytotoxic agents and their targets on the cell cycle, as well as the governing pharmacokinetic principles can improve treatment delivery. The adjuvant treatment setting can overcome barriers such as hypoxia and genetically driven treatment resistance.PurposeThe purpose of this review is to present theoretical frameworks behind the chemoradiation paradigm and to describe current chemoradiation practices in radiation oncology.MethodologyA review was conducted using the US National Library of Medicine, National Institutes of Health database (PubMed) using the following search keywords: chemoradiation, spatial cooperation, chemotherapeutic agents, pharmacokinetics, anti-vascular agents, tumour vasculature and tumour hypoxia.Results and conclusionsCurrent research has reported several rationales for the beneficial combination of radiation and chemotherapy to eradicate oncological diseases. Mechanisms of action and biological approaches are showing that concurrent treatments, as well as novel agents such as anti-vascular and anti-angiogenic agents may benefit improved treatment outcomes by reducing micro hypoxic environments in tumours. In addition, chemotherapy administered in tandem with radiation enhances cell-killing effects by targeting the cell cycle.

After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 22-30 ◽  
Author(s):  
Martha Wadleigh ◽  
Daniel J. DeAngelo ◽  
James D. Griffin ◽  
Richard M. Stone
Keyword(s):  
Cell Growth ◽  
Small Molecules ◽  
Chronic Myelogenous Leukemia ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Hematologic Malignancies ◽  
Myelogenous Leukemia ◽  
Pathologic Feature ◽  
Growth And Survival ◽  
Tyrosine Residues

AbstractTyrosine kinases phosphorylate proteins on tyrosine residues, producing a biologic signal that influences many aspects of cellular function including cell growth, proliferation, differentiation, and death. Constitutive or unregulated activity through mutation or overexpression of these enzymes is a common pathologic feature in many acute and chronic leukemias. Inhibition of tyrosine kinases represents a strategy to disrupt signaling pathways that promote neoplastic growth and survival in hematologic malignancies and likely in other neoplasias as well. This review focuses on tyrosine kinases that have been implicated in the pathogenesis of hematologic diseases other than chronic myelogenous leukemia and discusses the evidence for the use of small molecules to target these kinases.

scholarly journals Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

2014 ◽  
Vol 24 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Angeles Alvarez Secord ◽  
Deanna Teoh ◽  
Jingquan Jia ◽  
Andrew B. Nixon ◽  
Lisa Grace ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Combination Index ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Ovarian Cancer Cells ◽  
Response Curves ◽  
Pathway Activation ◽  
Skov3 Cells

PurposeThis study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.MethodsCells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.ResultsIn the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%–33%; P = 0.002 to 0.04) and p-paxicillin (6%–19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49–0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49–2.27).ConclusionsDasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

scholarly journals Comprehensive Analysis of Chemotherapeutic Agents THAT Induce Infectious Neutropenia

2021 ◽  
Vol 14 (7) ◽  
pp. 681
Author(s):  
Mashiro Okunaka ◽  
Daisuke Kano ◽  
Reiko Matsui ◽  
Toshikatsu Kawasaki ◽  
Yoshihiro Uesawa
Keyword(s):  
Chemotherapy Regimen ◽  
Alkylating Agents ◽  
Univariate Analysis ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Chemotherapeutic Agents ◽  
Comprehensive Analysis ◽  
Cytotoxic Agents ◽  
Underweight Patients ◽  
Using Data

Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring.

scholarly journals Bioactive Secondary Metabolites of the Genus Diaporthe and Anamorph Phomopsis from Terrestrial and Marine Habitats and Endophytes: 2010–2019

2021 ◽  
Vol 9 (2) ◽  
pp. 217
Author(s):  
Tang-Chang Xu ◽  
Yi-Han Lu ◽  
Jun-Fei Wang ◽  
Zhi-Qiang Song ◽  
Ya-Ge Hou ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Small Molecules ◽  
Host Plants ◽  
Plant Pathogens ◽  
Bioactive Metabolites ◽  
Drug Candidates ◽  
The Past ◽  
Marine Habitats ◽  
Bioactive Secondary Metabolites ◽  
Unidentified Species

The genus Diaporthe and its anamorph Phomopsis are distributed worldwide in many ecosystems. They are regarded as potential sources for producing diverse bioactive metabolites. Most species are attributed to plant pathogens, non-pathogenic endophytes, or saprobes in terrestrial host plants. They colonize in the early parasitic tissue of plants, provide a variety of nutrients in the cycle of parasitism and saprophytism, and participate in the basic metabolic process of plants. In the past ten years, many studies have been focused on the discovery of new species and biological secondary metabolites from this genus. In this review, we summarize a total of 335 bioactive secondary metabolites isolated from 26 known species and various unidentified species of Diaporthe and Phomopsis during 2010–2019. Overall, there are 106 bioactive compounds derived from Diaporthe and 246 from Phomopsis, while 17 compounds are found in both of them. They are classified into polyketides, terpenoids, steroids, macrolides, ten-membered lactones, alkaloids, flavonoids, and fatty acids. Polyketides constitute the main chemical population, accounting for 64%. Meanwhile, their bioactivities mainly involve cytotoxic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, anti-algae, phytotoxic, and enzyme inhibitory activities. Diaporthe and Phomopsis exhibit their potent talents in the discovery of small molecules for drug candidates.

scholarly journals GENETIC INVOLVEMENT OF INTERLEUKIN 4 FOR ASTHMA AND IDENTIFICATION OF POTENTIAL PHYTOCHEMICAL SCAFFOLD THROUGH MOLECULAR DOCKING STUDIES

2018 ◽  
Vol 10 (1) ◽  
pp. 43 ◽  
Author(s):  
S. Sarithamol ◽  
Divya V. ◽  
Sunitha V. R. ◽  
Suchitra Surendran ◽  
V. L. Pushpa ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Small Molecules ◽  
In Silico ◽  
Mutational Analysis ◽  
Chromosome Region ◽  
Specific Treatment ◽  
Docking Studies ◽  
Interleukin 4 ◽  
Receptor Interaction ◽  
Drug Candidates

Objective: Interleukin 4, an important cytokine, has the major role in the immunomodulatory responses associated with asthma. The present study focused on the involvement of single nucleotide polymorphism variation (SNP) of interleukin 4 (IL4) in the development of disease, asthma and designing small molecules for the inhibition of IL4 through in silico strategy.Methods: Identification of disease causing SNP will be a wise approach towards the phenotype specific treatment. A human origin deleterious no synonymous SNP of IL4 were found out in the chromosome region 5q31-q33 (rs199929962) (T/C). Proteins of the corresponding nucleotide variation were identified and were subjected to characterization studies for selecting the most appropriate one for further mutational analysis and molecular docking studies.Results: Influence of microbes on SNP variation of IL4 gene leading to asthma was found to be insignificant by metagenomic studies. Gene responsive drugs were identified through environmental factor analysis. The drug candidates including corticosteroids were subjected to protein interaction studies by in silico means. The pharmacophoric feature derived from drug receptor interaction was utilized for virtual screening on a dataset of anti-inflammatory phytomolecules. The scaffolds of ellagic acid and quercetin were identified as potential nonsteroidal entities which can shield the asthmatic activities.Conclusion: Developing small molecules using these scaffolds taking interleukin 4 as a target will be an adequate solution for steroid resistant asthma.

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