scholarly journals KLIFS: an overhaul after the first 5 years of supporting kinase research

2020 ◽  
Vol 49 (D1) ◽  
pp. D562-D569
Author(s):  
Georgi K Kanev ◽  
Chris de Graaf ◽  
Bart A Westerman ◽  
Iwan J P de Esch ◽  
Albert J Kooistra
Keyword(s):  
Kinase Inhibitors ◽  
Ligand Interaction ◽  
The Past ◽  
Structural Database ◽  
Approved Drugs ◽  
Interaction Fingerprints ◽  
Prime Target ◽  
Complete Overhaul ◽  
Programmatic Access ◽  
Systematic Collection

Abstract Kinases are a prime target of drug development efforts with >60 drug approvals in the past two decades. Due to the research into this protein family, a wealth of data has been accumulated that keeps on growing. KLIFS—Kinase–Ligand Interaction Fingerprints and Structures—is a structural database focusing on how kinase inhibitors interact with their targets. The aim of KLIFS is to support (structure-based) kinase research through the systematic collection, annotation, and processing of kinase structures. Now, 5 years after releasing the initial KLIFS website, the database has undergone a complete overhaul with a new website, new logo, and new functionalities. In this article, we start by looking back at how KLIFS has been used by the research community, followed by a description of the renewed KLIFS, and conclude with showcasing the functionalities of KLIFS. Major changes include the integration of approved drugs and inhibitors in clinical trials, extension of the coverage to atypical kinases, and a RESTful API for programmatic access. KLIFS is available at the new domain https://klifs.net.

Synthesis of Drugs and Biorelevant N-heterocycles Employing Recent Advances in C-N Bond Formation

2020 ◽  
Vol 24 (20) ◽  
pp. 2293-2340
Author(s):  
Firdoos Ahmad Sofi ◽  
Prasad V. Bharatam
Keyword(s):  
Kinase Inhibitors ◽  
Bond Formation ◽  
Comprehensive Review ◽  
Biologically Relevant ◽  
Lead Compounds ◽  
Heterocyclic Molecules ◽  
The Past ◽  
Anti Cancer ◽  
Modern Methods ◽  
Bond Formation Reactions

C-N bond formation is a particularly important step in the generation of many biologically relevant heterocyclic molecules. Several methods have been reported for this purpose over the past few decades. Well-known named reactions like Ullmann-Goldberg coupling, Buchwald-Hartwig coupling and Chan-Lam coupling are associated with the C-N bond formation reactions. Several reviews covering this topic have already been published. However, no comprehensive review covering the synthesis of drugs/ lead compounds using the C-N bond formation reactions was reported. In this review, we cover many modern methods of the C-N bond formation reactions, with special emphasis on metal-free and green chemistry methods. We also report specific strategies adopted for the synthesis of drugs, which involve the C-N bond formation reactions. Examples include anti-cancer, antidepressant, anti-inflammatory, anti-atherosclerotic, anti-histaminic, antibiotics, antibacterial, anti-rheumatic, antiepileptic and anti-diabetic agents. Many recently developed lead compounds generated using the C-N bond formation reactions are also covered in this review. Examples include MAP kinase inhibitors, TRKs inhibitors, Polo-like Kinase inhibitors and MPS1 inhibitors.

scholarly journals Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

2021 ◽  
Vol 22 (6) ◽  
pp. 3117
Author(s):  
Loredana Lorusso ◽  
Virginia Cappagli ◽  
Laura Valerio ◽  
Carlotta Giani ◽  
David Viola ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Progression Free Survival ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers ◽  
Approved Drugs ◽  
New Generation ◽  
Systemic Therapies

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

scholarly journals Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 330
Author(s):  
Mohammed I. El-Gamal ◽  
Seyed-Omar Zaraei ◽  
Moustafa M. Madkour ◽  
Hanan S. Anbar
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Agents ◽  
Current Status ◽  
Pyrazole Derivatives ◽  
Chronological Order ◽  
Pharmacological Activities ◽  
The Past ◽  
Cancer Types ◽  
Privileged Scaffold ◽  
Almost All

Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011–2020).

scholarly journals Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain

2021 ◽  
Vol 118 (10) ◽  
pp. e2016265118
Author(s):  
Mahmoud S. Ahmed ◽  
Ping Wang ◽  
Ngoc Uyen Nhi Nguyen ◽  
Yuji Nakada ◽  
Ivan Menendez-Montes ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Therapeutic Option ◽  
Atp Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

scholarly journals Immunotherapy in hematological malignancies: recent advances and open questions

Immunotherapy ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 1215-1229
Author(s):  
Essam A Tawfik ◽  
Norah A Aldrak ◽  
Shahad H Albrahim ◽  
Dunia A Alzahrani ◽  
Haya A Alfassam ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Hematopoietic Malignancy ◽  
Hematopoietic Malignancies ◽  
The Past ◽  
Open Questions ◽  
Cell Immunotherapy ◽  
Different Types ◽  
Us Fda ◽  
Approved Drugs ◽  
Fda Approved Drugs

Over recent years, tremendous advances in immunotherapy approaches have been observed, generating significant clinical progress. Cancer immunotherapy has been shown, in different types of blood cancers, to improve the overall survival of patients. Immunotherapy treatment of hematopoietic malignancies is a newly growing field that has been accelerating over the past years. Several US FDA approved drugs and cell-based therapies are being exploited in the late stage of clinical trials. This review attempt to highlight and discuss the numerous innovative immunotherapy approaches of hematopoietic malignancy ranging from nonmyeloablative transplantation, T-cell immunotherapy, natural killer cells and immune agonist to monoclonal antibodies and vaccination. In addition, a brief discussion on the future advances and accomplishments required to counterpart the current immunotherapeutic approaches for hematopoietic malignancies were also highlighted.

scholarly journals A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001263
Author(s):  
Alba Corman ◽  
Dimitris C. Kanellis ◽  
Patrycja Michalska ◽  
Maria Häggblad ◽  
Vanesa Lafarga ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Mrna Translation ◽  
Mtor Signaling Pathway ◽  
Mechanism Of Toxicity ◽  
Sphingosine Kinases ◽  
Chemical Screen ◽  
Approved Drugs ◽  
Very High

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.

Is Homeopathy More Effective Now Than a Hundred Years Ago?

2021 ◽  
Vol 34 (02) ◽  
pp. 123-129
Author(s):  
Lex Rutten ◽  
Raj Kumar Manchanda ◽  
José Eizayaga
Keyword(s):  
Statistical Analysis ◽  
Data Management ◽  
Effective Treatment ◽  
Past Century ◽  
Scientific Level ◽  
Amount Of Information ◽  
The Past ◽  
Treatment Data ◽  
Management Techniques ◽  
Systematic Collection

AbstractDuring the past century, the amount of information about homeopathic medicines has grown dramatically. However, the recent coronavirus disease 2019 pandemic has shown that homeopathic practitioners do not use more medicines than a century ago and they seem to use less symptoms to find the proper medicine. This could be explained by the fact that the more than a hundred years old repertory was flawed from the beginning and that more information in the repertory leads the practitioner astray in an increasingly complex labyrinth of data.This can be resolved by applying modern data management techniques based on systematic collection of treatment data and statistical analysis of the data. Homeopathic practitioners should collect these data avoiding bias. This requires additional training of practitioners, which should also result in a higher scientific level of homeopathic practice and increasingly effective treatment as the database grows.

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