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Special Issue "Kinase Inhibitors"

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

Deadline for manuscript submissions: closed (15 July 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Pierre Koch

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Website | E-Mail
Interests: protein kinase inhibitors; CNS diseases; synthetic organic chemistry; natural products
Guest Editor
Prof. Dr. Stefan Laufer

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Website | E-Mail
Interests: academic drug discovery; anti-inflammatories; protein kinases

Special Issue Information

Dear Colleagues,

Kinases are a large and diverse multi-gene family of enzymes that catalyze the transfer of γ-phosphate of ATP onto hydroxyl groups of substrates. They are involved in numerous cell-signaling pathways. Disease might arise when deregulation or mutation of a kinase takes place. Therefore, kinases are promising drug targets for the treatment of a number of disorders, e.g., cancer, autoimmune diseases, inflammation, neurodegenerative diseases and diabetes. To date, more than 30 protein kinase inhibitors are approved, two-thirds of which were launched onto the market within the last five years. Most of them are tyrosine kinase inhibitors with low selectivity used for treatment of cancer. The design of highly selective kinase inhibitors both as tools and probes, and as potential therapeutics, remains still challenging for medicinal chemists.

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 kinase inhibitors. Research manuscripts, as well as a limited number of review manuscripts, are welcome.

Prof. Dr. Pierre Koch
Prof. Dr. Stefan Laufer
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 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

  • Kinase inhibitors
  • Medicinal chemistry
  • Drug discovery
  • Rational design
  • Structure-based design
  • Selectivity
  • Reversible inhibitors
  • Covalent inhibitors

Published Papers (10 papers)

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Research

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Open AccessArticle From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
Molecules 2017, 22(10), 1729; doi:10.3390/molecules22101729
Received: 13 September 2017 / Revised: 5 October 2017 / Accepted: 10 October 2017 / Published: 14 October 2017
Cited by 1 | PDF Full-text (1554 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole ML3403 (4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)-N-(1-phenylethyl)pyridin-2-amine) undergoes rapid oxidation to the sulfoxide. Replacing the sulfur atom present in the two potent p38α mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 (2-((5-(4-fluorophenyl)-4-(2-((3-methylbutan-2-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)thio)ethan-1-ol)
[...] Read more.
In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole ML3403 (4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)-N-(1-phenylethyl)pyridin-2-amine) undergoes rapid oxidation to the sulfoxide. Replacing the sulfur atom present in the two potent p38α mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 (2-((5-(4-fluorophenyl)-4-(2-((3-methylbutan-2-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)thio)ethan-1-ol) by a methylene group resulted in 2-alkylimidazole derivatives 1 and 2, respectively, having a remarkably improved metabolic stability. The 2-alkylimidazole analogs 1 and 2 showed 20% and 10% biotransformation after 4 h of incubation with human liver microsomes, respectively. They display a 4-fold increased binding affinity towards the target kinase as well as similar in vitro potency and ex vivo efficacy relative to their 2-alkylsulfanylimidazole counterparts ML3403 and LN950. For example, 2-alkylimidazole 2, the analog of LN950, inhibits both the p38α MAP kinase as well as the LPS-stimulated tumor necrosis factor-α release from human whole blood in the low double-digit nanomolar range. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessArticle Methylisoindigo and Its Bromo-Derivatives Are Selective Tyrosine Kinase Inhibitors, Repressing Cellular Stat3 Activity, and Target CD133+ Cancer Stem Cells in PDAC
Molecules 2017, 22(9), 1546; doi:10.3390/molecules22091546
Received: 7 August 2017 / Revised: 11 September 2017 / Accepted: 11 September 2017 / Published: 13 September 2017
PDF Full-text (3311 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Indirubin is an active component of the herbal ingredient ‘Danggui Longhui wan’, which was used for the treatment of inflammation and chronic myeloid leukemia in China. The recent study showed its derivative methylisoindigo (also known as meisoindigo) preferentially targeting cancer stem cells (CSCs)
[...] Read more.
Indirubin is an active component of the herbal ingredient ‘Danggui Longhui wan’, which was used for the treatment of inflammation and chronic myeloid leukemia in China. The recent study showed its derivative methylisoindigo (also known as meisoindigo) preferentially targeting cancer stem cells (CSCs) in interference with AMPK and LKB1, the cellular metabolic sensors. In this study, we screened the effect of meisoindigo on a panel of 300 protein kinases and found that it selectively inhibited Stat3-associated tyrosine kinases and further confirmed its activity in cell based assays. To gain a deeper insight into the structure–activity relationship we produced 7 bromo-derivatives exhausting the accessible positions on the bisindole backbone except for in the 4-position due to the space limitation. We compared their anti-proliferative effects on tumor cells. We found that 6-bromomeisoindigo showed improved toxicity in company with increased Stat3 inhibition. Moreover, we detected that 6-bromomeisoindigo induced apoptosis of 95% of CD133+ pancreatic cancer cells. Considering that CD133 is a common marker highly expressed in a range of CSCs, our results imply the potential application of 6-bromomeisoindigo for the treatment of CSCs in different types of cancers. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessArticle Synthesis and Evaluation of Novel 2-Pyrrolidone-Fused (2-Oxoindolin-3-ylidene)methylpyrrole Derivatives as Potential Multi-Target Tyrosine Kinase Receptor Inhibitors
Molecules 2017, 22(6), 913; doi:10.3390/molecules22060913
Received: 29 March 2017 / Revised: 21 May 2017 / Accepted: 29 May 2017 / Published: 31 May 2017
Cited by 1 | PDF Full-text (6621 KB) | HTML Full-text | XML Full-text
Abstract
Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for designing and synthesizing a series of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors.
[...] Read more.
Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for designing and synthesizing a series of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. The target compounds were obtained by condensation of 5-substituted oxindoles with N-substituted 2-pyrrolidone aldehyde 7 in satisfactory yields. Of these, 11 and 12 had the highest potency and, compared to sunitinib, showed: (1) significant increase in anti-proliferation of various cancer cells with a favorable selective index (SI); (2) higher inhibitory potency against both VEGFR-2 and PDGFRβ. The molecular modeling results showed that, in terms of VEGFR-2 binding, the synthesized products had a similar binding mode to sunitinib but with tighter interaction. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessArticle Assessing Scaffold Diversity of Kinase Inhibitors Using Alternative Scaffold Concepts and Estimating the Scaffold Hopping Potential for Different Kinases
Molecules 2017, 22(5), 730; doi:10.3390/molecules22050730
Received: 13 April 2017 / Revised: 26 April 2017 / Accepted: 1 May 2017 / Published: 3 May 2017
Cited by 1 | PDF Full-text (1141 KB) | HTML Full-text | XML Full-text
Abstract
Publicly available kinase inhibitors provide a large source of information for structure–activity relationship analysis and kinase drug design. In this study, publicly available inhibitors of the human kinome were collected and analog series formed by kinase inhibitors systematically identified. Then, alternative scaffold concepts
[...] Read more.
Publicly available kinase inhibitors provide a large source of information for structure–activity relationship analysis and kinase drug design. In this study, publicly available inhibitors of the human kinome were collected and analog series formed by kinase inhibitors systematically identified. Then, alternative scaffold concepts were applied to assess diversity and promiscuity of kinase inhibitors. Over the past two years, the number of publicly available kinase inhibitors with high-confidence activity data more than doubled, but coverage of the human kinome only slightly increased. Approximately 70% of current kinase inhibitors belonged to analog series. However, the detectable degree of promiscuity among these kinase inhibitors remained low. Approximately 76% of all inhibitors were only annotated with a single kinase, compared to ~70% two years ago. For many kinases, the assessment of scaffold diversity among their inhibitors and the distribution of differently defined scaffolds over analog series made it possible to assess scaffold hopping potential. Our analysis revealed that the consideration of conventional compound-based scaffolds most likely leads to an overestimation of scaffold hopping frequency, at least for compounds forming analog series. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessArticle Discovery and Biological Evaluation of a Series of Pyrrolo[2,3-b]pyrazines as Novel FGFR Inhibitors
Molecules 2017, 22(4), 583; doi:10.3390/molecules22040583
Received: 26 January 2017 / Revised: 31 March 2017 / Accepted: 3 April 2017 / Published: 5 April 2017
PDF Full-text (6360 KB) | HTML Full-text | XML Full-text
Abstract
Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified
[...] Read more.
Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3-b]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessArticle Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK
Molecules 2017, 22(4), 522; doi:10.3390/molecules22040522
Received: 31 January 2017 / Revised: 17 March 2017 / Accepted: 20 March 2017 / Published: 24 March 2017
Cited by 1 | PDF Full-text (8128 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and
[...] Read more.
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50 CK1δ = 4 nM, IC50 CK1ε = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ε = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 µM) and Panc89 (EC50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessArticle CDC25 Inhibition in Acute Myeloid Leukemia–A Study of Patient Heterogeneity and the Effects of Different Inhibitors
Molecules 2017, 22(3), 446; doi:10.3390/molecules22030446
Received: 25 January 2017 / Revised: 1 March 2017 / Accepted: 6 March 2017 / Published: 11 March 2017
Cited by 2 | PDF Full-text (11700 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cell division cycle 25 (CDC25) protein phosphatases regulate cell cycle progression through the activation of cyclin-dependent kinases (CDKs), but they are also involved in chromatin modulation and transcriptional regulation. CDC25 inhibition is regarded as a possible therapeutic strategy for the treatment of human
[...] Read more.
Cell division cycle 25 (CDC25) protein phosphatases regulate cell cycle progression through the activation of cyclin-dependent kinases (CDKs), but they are also involved in chromatin modulation and transcriptional regulation. CDC25 inhibition is regarded as a possible therapeutic strategy for the treatment of human malignancies, including acute myeloid leukemia (AML). We investigated the in vitro effects of CDC25 inhibitors on primary human AML cells derived from 79 unselected patients in suspension cultures. Both the previously well-characterized CDC25 inhibitor NSC95397, as well as five other inhibitors (BN82002 and the novel small molecular compounds ALX1, ALX2, ALX3, and ALX4), only exhibited antiproliferative effects for a subset of patients when tested alone. These antiproliferative effects showed associations with differences in genetic abnormalities and/or AML cell differentiation. However, the responders to CDC25 inhibition could be identified by analysis of global gene expression profiles. The differentially expressed genes were associated with the cytoskeleton, microtubules, and cell signaling. The constitutive release of 28 soluble mediators showed a wide variation among patients and this variation was maintained in the presence of CDC25 inhibition. Finally, NSC95397 had no or only minimal effects on AML cell viability. In conclusion, CDC25 inhibition has antiproliferative effects on primary human AML cells for a subset of patients, and these patients can be identified by gene expression profiling. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Review

Jump to: Research

Open AccessReview Current Development Status of MEK Inhibitors
Molecules 2017, 22(10), 1551; doi:10.3390/molecules22101551
Received: 9 August 2017 / Revised: 11 September 2017 / Accepted: 12 September 2017 / Published: 26 September 2017
PDF Full-text (1109 KB) | HTML Full-text | XML Full-text
Abstract
The current development status of mitogen-activated protein kinase kinase (MEK) inhibitors, including the preclinical data and clinical study progress, has been summarized in this review. Different MEK inhibitors, possessing specific physicochemical properties and bioactivity characteristics, may provide different options for patients seeking treatment
[...] Read more.
The current development status of mitogen-activated protein kinase kinase (MEK) inhibitors, including the preclinical data and clinical study progress, has been summarized in this review. Different MEK inhibitors, possessing specific physicochemical properties and bioactivity characteristics, may provide different options for patients seeking treatment for cancer. Moreover, the combination of the MEK inhibitors with other therapies—such as chemotherapy, targeted therapy, and immunotherapy—may be a promising approach for clinical use. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessReview The Role of Kinase Modulators in Cellular Senescence for Use in Cancer Treatment
Molecules 2017, 22(9), 1411; doi:10.3390/molecules22091411
Received: 11 July 2017 / Revised: 22 August 2017 / Accepted: 24 August 2017 / Published: 25 August 2017
PDF Full-text (1144 KB) | HTML Full-text | XML Full-text
Abstract
Recently, more than 30 small molecules and eight monoclonal antibodies that modulate kinase signaling have been approved for the treatment of several pathological conditions, including cancer, idiopathic pulmonary fibrosis, and rheumatoid arthritis. Among them, kinase modulators have been a primary focus for use
[...] Read more.
Recently, more than 30 small molecules and eight monoclonal antibodies that modulate kinase signaling have been approved for the treatment of several pathological conditions, including cancer, idiopathic pulmonary fibrosis, and rheumatoid arthritis. Among them, kinase modulators have been a primary focus for use in cancer treatment. Cellular senescence is believed to protect cells from tumorigenesis by irreversibly halting cell cycle progression and avoiding the growth of damaged cells and tissues. Senescence can also contribute to tumor suppression and be utilized as a mechanism by anti-cancer agents. Although the role of kinase modulators in cancer treatment and their effects on senescence in tumor development have been extensively studied, the relationship between kinase modulators for cancer treatment and senescence has not been fully discussed. In this review, we discuss the pro- and anti-tumorigenesis functions of senescence and summarize the key roles of kinase modulators in the regulation of senescence against tumors. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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Open AccessReview Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease
Molecules 2017, 22(8), 1287; doi:10.3390/molecules22081287
Received: 8 July 2017 / Revised: 27 July 2017 / Accepted: 1 August 2017 / Published: 2 August 2017
Cited by 1 | PDF Full-text (2375 KB) | HTML Full-text | XML Full-text
Abstract
P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on
[...] Read more.
P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on the underlying biology of AD in cellular and animal models have indicated that p38 MAPK is capable of orchestrating diverse events related to AD, such as tau phosphorylation, neurotoxicity, neuroinflammation and synaptic dysfunction. Thus, the inhibition of p38 MAPK is considered a promising strategy for the treatment of AD. In this review, we summarize recent advances in the targeting of p38 MAPK as a potential strategy for the treatment of AD and envision possibilities of p38 MAPK inhibitors as a fundamental therapeutics for AD. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
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