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Small Molecule Inhibitors of Protein Kinases
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Small Molecule Inhibitors of Protein Kinases

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 10517

Special Issue Editors

Prof. Dr. Stefan Laufer

E-Mail Website
Guest Editor
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Interests: academic drug discovery; anti-inflammatories; anti-cancer; autoimmune; protein kinases; protein-protein interaction
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Pierre Koch

E-Mail Website
Guest Editor
Department of Pharmaceutical and Medicinal Chemistry II, Institute of Pharmacy, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Interests: protein kinase inhibitors; CNS diseases; synthetic organic chemistry; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein kinases represent a large and diverse multi-gene family of enzymes that are involved in numerous cell signaling pathways. They catalyze the transfer of the γ-phosphate group from its natural co-substrate adenosine triphosphate to the free hydroxyl group of a serine, threonine, or tyrosine side chain. Diseases might arise when deregulation or mutation of a kinase takes place.

Kinases are promising drug targets for the treatment of several diseases, such as cancer, inflammation, autoimmune pathologies, or neurodegenerative diseases. Since the approval of imatinib in 2001, 59 kinase inhibitors have been introduced to the market, and numerous kinase inhibitors are currently in different stages of clinical trials.

Both structural data as well as the high-quality kinase probe programs have kept pushing forward the identification of new kinase targets as well as the design of novel kinase inhibitors in recent years. The numbers of reported reversible, covalent, and allosteric small molecule kinase inhibitors has been continuously increasing in the last few years.

This Special Issue aims to attract all researchers working in this research field and will collect new findings and recent advances on the development, synthesis, and structure–activity relationships of novel small molecule kinase inhibitors as well as on novel approaches in protein kinase drug discovery. Research manuscripts as well as a limited number of review manuscripts are welcome.

Prof. Dr. Stefan Laufer
Prof. Dr. Pierre Koch
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (3 papers)

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Research

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26 pages, 3511 KiB  
Article
7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors
by Mehmet Karatas, Apirat Chaikuad, Bianca Berger, Michael H. G. Kubbutat, Frank Totzke, Stefan Knapp and Conrad Kunick
Molecules 2021, 26(6), 1611; https://doi.org/10.3390/molecules26061611 - 14 Mar 2021
Cited by 4 | Viewed by 3026
Abstract
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure [...] Read more.
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Protein Kinases)
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14 pages, 2564 KiB  
Article
The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts
by Christin Neuber, Alix Tröster, Reik Löser, Birgit Belter, Harald Schwalbe and Jens Pietzsch
Molecules 2020, 25(21), 5115; https://doi.org/10.3390/molecules25215115 - 3 Nov 2020
Cited by 3 | Viewed by 2967
Abstract
In a previous study, EphB4 was demonstrated to be a positive regulator of A375-melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVP-BHG712 (NVP), [...] Read more.
In a previous study, EphB4 was demonstrated to be a positive regulator of A375-melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVP-BHG712 (NVP), which was later identified as its regioisomer NVPiso. Since there have been reported significant differences between the inhibition profiles of NVP and NVPiso, we compared the influence of NVP and NVPiso on tumor characteristics under the same experimental conditions. Despite the different inhibitory profiles of NVP and NVPiso, the comparative study conducted here showed the same EphB4-induced effects in vivo as in the previous investigation. This confirmed the conclusion that EphB4-ephrinB2 reverse signaling is responsible for increased tumor growth as well as decreased tumor vascularization and perfusion. These results are further substantiated by microarrays showing differences between mock-transfected and EphB4-transfected (A375-EphB4) cells with respect to at least 9 angiogenesis-related proteins. Decreased expression of vascular endothelial growth factor (VEGF), angiotensin 1 (Ang-1), and protein kinase B (Akt/PKB), together with the increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor beta-2 (TGF-β2), is consistent with the impaired vascularization of A375-EphB4 xenografts. Functional overexpression of EphB4 in A375-EphB4 cells was confirmed by activation of a variety of signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT), rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase (Ras/Raf/MEK), and nuclear factor kappa-B (NFkB) pathways. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Protein Kinases)
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Review

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45 pages, 4704 KiB  
Review
An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors
by Chantalle Moolman, Rencia van der Sluis, Richard M. Beteck and Lesetja J. Legoabe
Molecules 2020, 25(21), 5182; https://doi.org/10.3390/molecules25215182 - 7 Nov 2020
Cited by 11 | Viewed by 3986
Abstract
Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination [...] Read more.
Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Protein Kinases)
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