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Special Issue "Kinase Inhibitors II"

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

Deadline for manuscript submissions: 28 February 2019

Special Issue Editor

Guest Editor
Prof. Dr. Christian Peifer

Department of Pharmaceutical Chemistry, Christian Albrechts University, Gutenbergstraße 76, 24118 Kiel, Germany
Website | E-Mail
Phone: +49 431 880 1137
Fax: +49 431 880 1352
Interests: design; synthesis and biological evaluation of protein kinase inhibitors

Special Issue Information

Dear Colleagues,

Since the discovery of protein phosphorylation as a post-translational modification in glycogen metabolism in the1960s, protein kinases (PK) and their opponents, phosphatases, have been crucial to many scientists. Approximately 2% of the human genome encodes for PKs, named the human “kinome”, consisting of 518 PKs and their splice variants. PKs typically use ATP for γ-phosphor-transfer reactions for OH-functions of serine, threonine, or tyrosine residues in proteins. In fact, the relatively simple attachment of a phosphate moiety induces critical conformational and functional changes of the substrate protein. Due to the powerful nature of protein modification involved in key cellular processes, such as signal transduction, cell cycle, metabolism, differentiation, and cell survival, PKs have to be strictly regulated in a physiological context. In contrast, their dysregulation leads to severe diseases, including cancer. In line with this notion, the first proto-oncogene c-SRC was identified as a non-receptor tyrosine kinase in 1978.

Today, PKs are validated and widely accepted targets for drug discovery, triggered significantly by the clinical success of imatinib in 2001. Thus far, more than 40 drugs have been FDA-approved and are on the market. The majority of compounds address tyrosine kinases, with their main therapeutical applications being cancer and inflammation. In addition to massive commercial drug discovery programs for the development of kinase inhibitors, academia has contributed a solid part to today´s knowledge on PK and their inhibitors. A wealth of biological studies towards the validation of PKs as drug targets, hit-compounds, lead structures, pharmacological tools, and ligand–protein complexes for the development of novel PK inhibitors are reported in literature. The topics cover various scientific areas, including molecular biology, biological and medicinal chemistry, and clinical applications.

This Special Issue of Molecules will focus on the exciting area of protein kinases and novel approaches in PK drug discovery.

Prof. Dr. Christian Peifer
Guest Editor

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 papers will be 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 monthly 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 1800 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.

Keywords

  • protein phosphorylation
  • signal transduction
  • small molecule kinase inhibitors (smKI)
  • receptor tyrosine kinases
  • serin-threonine kinases
  • pseudokinases
  • Type I-VI
  • DFGin
  • DFGout
  • hinge-binder
  • gatekeeper-residue
  • ATP competitive/alosteric/covalent inhibition
  • kinome-screening selectivity
  • 518 human protein kinases
  • in-vitro activity/in-vivo efficacy
  • mutated kinases,
  • rational structure- based design
  • medicinal chemistry/drug discovery
  • targeted therapy
  • personalized medicine

Published Papers (1 paper)

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Research

Open AccessArticle Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo
Molecules 2018, 23(10), 2643; https://doi.org/10.3390/molecules23102643
Received: 28 August 2018 / Revised: 4 October 2018 / Accepted: 11 October 2018 / Published: 15 October 2018
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Abstract
Dysregulation of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling pathway is frequently observed in multiple human malignancies, and thus, therapeutic strategies targeting FGFs and FGFRs in human cancer are being extensively explored. We observed the activation of the FGF/FGFR-signaling pathway
[...] Read more.
Dysregulation of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling pathway is frequently observed in multiple human malignancies, and thus, therapeutic strategies targeting FGFs and FGFRs in human cancer are being extensively explored. We observed the activation of the FGF/FGFR-signaling pathway in imatinib (IM)-resistant gastrointestinal stromal tumor (GIST) cells. Furthermore, we found that the activation of FGFR signaling has a significant impact on IM resistance in GISTs in vitro. Next, we tested the efficacy of BGJ398, a potent and selective FGFR1–3 inhibitor, in xenograft models of GISTs exhibiting secondary IM resistance due to receptor-tyrosine kinase (RTK) switch (loss of c-KIT/gain of FGFR2a). Five to eight-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with GIST T-1R cells. Mice were randomized as control (untreated), IM, BGJ398, or a combination and treated orally for 12 days. IM had a moderate effect on tumor size, thus revealing GIST resistance to IM. Similarly, a minor regression in tumor size was observed in BGJ398-treated mice. Strikingly, a 90% decrease in tumor size was observed in mice treated with a combination of IM and BGJ398. Treatment with BGJ398 and IM also induced major histopathologic changes according to a previously defined histopathologic response score and resulted in massive myxoid degeneration. This was associated with increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, treatment with BGJ398 and IM significantly reduced the proliferative activity of tumor cells as measured by positivity for Ki-67 staining. In conclusion, inhibition of FGFR signaling substantially inhibited the growth of IM-resistant GISTs in vitro and showed potent antitumor activity in an IM-resistant GIST model via the inhibition of proliferation, tumor growth, and the induction of apoptosis, thereby suggesting that patients with advanced and metastatic GISTs exhibiting IM resistance might benefit from therapeutic inhibition of FGFR signaling. Full article
(This article belongs to the Special Issue Kinase Inhibitors II)
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