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Special Issue "Marine Compounds as Protein Kinase Inhibitors"

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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 January 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Christian Peifer (Website)

Department of Pharmaceutical Chemistry, Christian Albrechts University, Gutenbergstraße 76, 24118 Kiel, Germany
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,

Biologically active marine derived compounds have been shown to represent an interesting source of novel compounds that are protein kinase inhibitors (PKI). Protein kinases (PK) are validated targets for drug discovery, particularly in cancer. Thus far, a number of potent natural product PKI’s and PK modulators have been isolated including secondary metabolites from marine organisms and these have been useful as pharmacological tools and lead structures to develop novel PKI’s.

Despite their original biological functions, marine compounds often have non-optimal properties when evaluated in vivo such as inappropriate pharmacokinetic properties, or structural complexity that makes them difficult for scale-up synthesis. Therefore, significant medicinal chemistry is often required in order to optimize these compounds for drug discovery purposes. Despite these challenges, a large pool of marine organisms is available to search for novel compounds that could act as novel PKI’s.

Staurosporine, a nonspecific and thus toxic PKI inhibits many of the 518 human PK with high potency and this represents an early and well-known natural product derived PKI. The use of Staurosporine has led to a wealth of ligand-PK structures, providing significant structure-based design opportunities towards more specific PKI’s. The marine-sponge derived Hymenialdisines were discovered as potent inhibitors of PK involved in inflammation, thus blocking interleukin-2/TNF-alpha cytokine production. Subsequently, Hymenialdisine-derived indoloazepine derivatives were optimized leading to selective CHK1 and CHK2 inhibitors. The marine sponge-derived bis-indole alkaloide Fascaplysin, was reported to be a selective CDK4/cyclin D1 ligand. Furthermore, the macrolid lactone Bryostatin-1 produced by Bryozoa, marine invertebrate animals was characterized as a potent modulator of Protein Kinase C. These examples illustrate the importance of marine-derived PKI’s, and no-doubt more novel compounds will be discovered from the oceans in the future.

This Special Issue of Marine Drugs will focus on the exciting area of marine-derived compounds which may allow for novel approaches in PKI drug discovery.


Prof. Dr. Christian Peifer
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs 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).

Keywords

  • protein kinase inhibitors (PKI)
  • small molecule PKI (smPKI)
  • marine sponge metabolites
  • potency and selectivity
  • Staurosporine bisindole alkaloids
  • bryostatin-1
  • hymenialdisine
  • fascaplysin
  • anti-cancer activity
  • antibiotic activity

Published Papers (4 papers)

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Research

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Open AccessArticle Novel Adociaquinone Derivatives from the Indonesian Sponge Xestospongia sp.
Mar. Drugs 2015, 13(5), 2617-2628; doi:10.3390/md13052617
Received: 3 March 2015 / Revised: 2 April 2015 / Accepted: 3 April 2015 / Published: 28 April 2015
PDF Full-text (798 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Seven new adociaquinone derivatives, xestoadociaquinones A (1a), B (1b), 14-carboxy-xestoquinol sulfate (2) and xestoadociaminals A–D (3a, 3c, 4a, 4c), together with seven known compounds (511) were isolated [...] Read more.
Seven new adociaquinone derivatives, xestoadociaquinones A (1a), B (1b), 14-carboxy-xestoquinol sulfate (2) and xestoadociaminals A–D (3a, 3c, 4a, 4c), together with seven known compounds (511) were isolated from an Indonesian marine sponge Xestospongia sp. Their structures were elucidated by extensive 1D and 2D NMR and mass spectrometric data. All the compounds were evaluated for their potential inhibitory activity against eight different protein kinases involved in cell proliferation, cancer, diabetes and neurodegenerative disorders as well as for their antioxidant and antibacterial activities. Full article
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)
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Open AccessArticle Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors
Mar. Drugs 2013, 11(9), 3209-3223; doi:10.3390/md11093209
Received: 7 June 2013 / Revised: 1 August 2013 / Accepted: 8 August 2013 / Published: 26 August 2013
Cited by 6 | PDF Full-text (807 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge [...] Read more.
In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge alkaloids) by Molecular Modeling studies as core binding motif in the ATP pocket of receptor tyrosine kinases (RTK), which are validated drug targets for the treatment of various neoplastic diseases. Structure-based design studies on a human RTK member PDGFR (platelet-derived growth factor receptor) suggested a straight forward lead optimization strategy. Accordingly, we focused on a Medicinal Chemistry project to develop pyrazin-2(1H)-ones as optimized PDGFR binders. In order to reveal Structure-Activity-Relationships (SAR), we established a flexible synthetic route via microwave mediated ring closure to asymmetric 3,5-substituted pyrazin-2(1H)-ones and produced a set of novel compounds. Herein, we identified highly potent PDGFR binders with IC50 values in an enzymatic assay below µM range, and possessing significant activity against PDGFR dependent cancer cells. Thus, marine hamacanthin-derived pyrazin-2(1H)-ones showing interesting properties as lead for their further development towards potent PDGFR-inhibitors. Full article
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)
Open AccessArticle Predictive Factors of Sensitivity to Elisidepsin, a Novel Kahalalide F-Derived Marine Compound
Mar. Drugs 2013, 11(3), 944-959; doi:10.3390/md11030944
Received: 28 December 2012 / Revised: 21 January 2013 / Accepted: 22 February 2013 / Published: 20 March 2013
Cited by 9 | PDF Full-text (903 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel [...] Read more.
Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings. Full article
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)

Review

Jump to: Research

Open AccessReview Marine-Derived Angiogenesis Inhibitors for Cancer Therapy
Mar. Drugs 2013, 11(3), 903-933; doi:10.3390/md11030903
Received: 4 February 2013 / Revised: 25 February 2013 / Accepted: 1 March 2013 / Published: 15 March 2013
Cited by 16 | PDF Full-text (1747 KB) | HTML Full-text | XML Full-text
Abstract
Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique [...] Read more.
Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs. Full article
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)

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