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Special Issue "Kinase Inhibitor Chemistry"

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

Deadline for manuscript submissions: closed (15 August 2016)

Special Issue Editor

Guest Editor
Prof. James W. Leahy

Chemistry Department, University of South Florida, USA
Website | E-Mail
Interests: drug discovery, cancer, inflammation, neurological diseases, cardiovascular disease, kinase inhibitors, natural products

Special Issue Information

Dear Colleagues,

The development of therapeutic agents that target the inhibition of kinases has proven to be a fruitful endeavor. More than two dozen agents have been approved by the U. S. FDA in the last fifteen years. While there is no longer a question as to whether kinases are valid targets, there are still a myriad of approaches for pursuing inhibitors that span selectivity and reversibility parameters. Additionally, the utility of kinase inhibitors has been demonstrated in a variety of indications, from cancer to inflammation and pulmonary disease. This Special Issue aims to highlight recent results in the identification and optimization of kinase inhibitors in the continued search for new medicinal agents.

Professor James W. Leahy
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

  • kinase inhibitor
  • drug discovery
  • lead optimization
  • cancer
  • cardiovascular disease
  • macular degeneration
  • neurological disorders
  • infectious disease
  • immunosuppression

Published Papers (10 papers)

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Research

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Open AccessArticle Hair Growth Promoting and Anticancer Effects of p21-activated kinase 1 (PAK1) Inhibitors Isolated from Different Parts of Alpinia zerumbet
Molecules 2017, 22(1), 132; doi:10.3390/molecules22010132
Received: 5 November 2016 / Revised: 5 January 2017 / Accepted: 8 January 2017 / Published: 14 January 2017
PDF Full-text (817 KB) | HTML Full-text | XML Full-text
Abstract
PAK1 (p21-activated kinase 1) is an emerging target for the treatment of hair loss (alopecia) and cancer; therefore, the search for PAK1 blockers to treat these PAK1-dependent disorders has received much attention. In this study, we evaluated the anti-alopecia and anticancer effects of
[...] Read more.
PAK1 (p21-activated kinase 1) is an emerging target for the treatment of hair loss (alopecia) and cancer; therefore, the search for PAK1 blockers to treat these PAK1-dependent disorders has received much attention. In this study, we evaluated the anti-alopecia and anticancer effects of PAK1 inhibitors isolated from Alpinia zerumbet (alpinia) in cell culture. The bioactive compounds isolated from alpinia were found to markedly promote hair cell growth. Kaempferol-3-O-β-d-glucuronide (KOG) and labdadiene, two of the isolated compounds, increased the proliferation of human follicle dermal papilla cells by approximately 117%–180% and 132%–226%, respectively, at 10–100 μM. MTD (2,5-bis(1E,3E,5E)-6-methoxyhexa-1,3,5-trien-1-yl)-2,5-dihydrofuran) and TMOQ ((E)-2,2,3,3-tetramethyl-8-methylene-7-(oct-6-en-1-yl)octahydro-1H-quinolizine) showed growth-promoting activity around 164% and 139% at 10 μM, respectively. The hair cell proliferation induced by these compounds was significantly higher than that of minoxidil, a commercially available treatment for hair loss. Furthermore, the isolated compounds from alpinia exhibited anticancer activity against A549 lung cancer cells with IC50 in the range of 67–99 μM. Regarding the mechanism underlying their action, we hypothesized that the anti-alopecia and anticancer activities of these compounds could be attributed to the inhibition of the oncogenic/aging kinase PAK1. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Open AccessArticle Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer
Molecules 2016, 21(11), 1462; doi:10.3390/molecules21111462
Received: 30 September 2016 / Revised: 26 October 2016 / Accepted: 29 October 2016 / Published: 2 November 2016
Cited by 2 | PDF Full-text (5564 KB) | HTML Full-text | XML Full-text
Abstract
Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this
[...] Read more.
Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFRT790M) (IC50 = 0.71 nM) over wild-type EGFR (IC50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFRT790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC50 value of 0.037 μM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFRT790M-mutated NSCLC. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Open AccessArticle Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors
Molecules 2016, 21(10), 1407; doi:10.3390/molecules21101407
Received: 10 September 2016 / Revised: 13 October 2016 / Accepted: 17 October 2016 / Published: 23 October 2016
Cited by 1 | PDF Full-text (3971 KB) | HTML Full-text | XML Full-text
Abstract
Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors.
[...] Read more.
Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H-indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30.2 nM. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Figure 1

Open AccessArticle Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors
Molecules 2016, 21(8), 1012; doi:10.3390/molecules21081012
Received: 2 June 2016 / Revised: 12 July 2016 / Accepted: 29 July 2016 / Published: 3 August 2016
Cited by 3 | PDF Full-text (3933 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against
[...] Read more.
A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against four cancer cell line variants (A549, MCF-7, HeLa, HepG2) with IC50 values of 0.46, 0.29, 0.15 and 0.21 μM respectively, which showed the most potent EGFR inhibition activities (IC50 = 0.08 μM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity and activity relationship (SAR) of these benzohydrazide derivatives. These results suggested that compound H20 may be a promising anticancer agent. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Open AccessArticle Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors
Molecules 2016, 21(7), 876; doi:10.3390/molecules21070876
Received: 5 June 2016 / Revised: 22 June 2016 / Accepted: 24 June 2016 / Published: 2 July 2016
Cited by 3 | PDF Full-text (4853 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A novel series of PI3Kβ (Phosphatidylinositol-3-kinases beta subunit) inhibitors with the structure of benzothiazole scaffold have been designed and synthesized. All the compounds have been evaluated for inhibitory activities against PI3Kα, β, γ, δ and mTOR (Mammalian target of rapamycin). Two superior compounds
[...] Read more.
A novel series of PI3Kβ (Phosphatidylinositol-3-kinases beta subunit) inhibitors with the structure of benzothiazole scaffold have been designed and synthesized. All the compounds have been evaluated for inhibitory activities against PI3Kα, β, γ, δ and mTOR (Mammalian target of rapamycin). Two superior compounds have been further evaluated for the IC50 values against PI3Ks/mTOR. The most promising compound 11 displays excellent anti-proliferative activity and selectivity in multiple cancer cell lines, especially in the prostate cancer cell line. Docking studies indicate the morpholine group in 2-position of benzothiazole is necessary for the potent antitumor activity, which confirms our design is reasonable. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Open AccessArticle Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α
Molecules 2016, 21(7), 857; doi:10.3390/molecules21070857
Received: 8 April 2016 / Revised: 23 June 2016 / Accepted: 23 June 2016 / Published: 29 June 2016
PDF Full-text (1611 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Phosphatidylinositol 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Liphagal, isolated from the marine sponge Aka coralliphaga, possesses the special “liphagane” meroterpenoid carbon skeleton and has been demonstrated as a PI3Kα inhibitor. Molecular docking and molecular dynamics simulations were
[...] Read more.
Phosphatidylinositol 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Liphagal, isolated from the marine sponge Aka coralliphaga, possesses the special “liphagane” meroterpenoid carbon skeleton and has been demonstrated as a PI3Kα inhibitor. Molecular docking and molecular dynamics simulations were performed to explore the dynamic behaviors of PI3Kα binding with liphagal, and free energy calculations and energy decomposition analysis were carried out by use of molecular mechanics/Poisson-Boltzmann (generalized Born) surface area (MM/PB(GB)SA) methods. The results reveal that the heteroatom rich aromatic D-ring of liphagal extends towards the polar region of the binding site, and the D-ring 15-hydroxyl and 16-hydroxyl form three hydrogen bonds with Asp810 and Tyr836. The cyclohexyl A-ring projects up into the upper pocket of the lipophilic region, and the hydrophobic/van der Waals interactions with the residues Met772, Trp780, Ile800, Ile848, Val850, Met922, Phe930, Ile932 could be the key interactions for the affinity of liphagal to PI3Kα. Thus, a new strategy for the rational design of more potent analogs of liphagal against PI3Kα is provided. Our proposed PI3Kα/liphagal binding mode would be beneficial for the discovery of new active analogs of liphagal against PI3Kα. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Open AccessArticle Synthesis and p38 Inhibitory Activity of Some Novel Substituted N,N′-Diarylurea Derivatives
Molecules 2016, 21(5), 677; doi:10.3390/molecules21050677
Received: 11 April 2016 / Revised: 22 April 2016 / Accepted: 12 May 2016 / Published: 23 May 2016
Cited by 3 | PDF Full-text (1858 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have identified a novel series of substituted N,N′-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were
[...] Read more.
We have identified a novel series of substituted N,N′-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were tested. Among these compounds, 25a inhibited the p38α enzyme with an IC50 value of 0.47 nM and a KD value of 1.54 × 10−8 and appears to be the most promising one in the series. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
Open AccessArticle The Guareschi Pyridine Scaffold as a Valuable Platform for the Identification of Selective PI3K Inhibitors
Molecules 2015, 20(9), 17275-17287; doi:10.3390/molecules200917275
Received: 13 July 2015 / Revised: 9 September 2015 / Accepted: 14 September 2015 / Published: 18 September 2015
PDF Full-text (1414 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound
[...] Read more.
A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3Kα isoform, maintaining a good inhibitory activity. Docking studies were also performed in order to rationalize its profile of selectivity. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Open AccessArticle Design, Synthesis and Biological Evaluation of Novel Substituted N,N′-Diaryl ureas as Potent p38 Inhibitors
Molecules 2015, 20(9), 16604-16619; doi:10.3390/molecules200916604
Received: 26 August 2015 / Revised: 7 September 2015 / Accepted: 9 September 2015 / Published: 11 September 2015
Cited by 1 | PDF Full-text (1255 KB) | HTML Full-text | XML Full-text
Abstract
A novel series of substituted N,N′-diaryl ureas that act as p38α inhibitors have been designed and synthesized based on two key residues (Gly110 and Thr106) that are different in p38α MAPK than in other kinases. Preliminary biological evaluation
[...] Read more.
A novel series of substituted N,N′-diaryl ureas that act as p38α inhibitors have been designed and synthesized based on two key residues (Gly110 and Thr106) that are different in p38α MAPK than in other kinases. Preliminary biological evaluation indicated that most compounds possessed good p38α inhibitory potencies. Among these compounds, 9g appeared to be the most powerful and is the main compound that we will study in the future. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Review

Jump to: Research

Open AccessReview Recent Advances in the Development and Application of Radiolabeled Kinase Inhibitors for PET Imaging
Molecules 2015, 20(12), 22000-22027; doi:10.3390/molecules201219816
Received: 22 October 2015 / Revised: 18 November 2015 / Accepted: 1 December 2015 / Published: 9 December 2015
Cited by 4 | PDF Full-text (7839 KB) | HTML Full-text | XML Full-text
Abstract
Over the last 20 years, intensive investigation and multiple clinical successes targeting protein kinases, mostly for cancer treatment, have identified small molecule kinase inhibitors as a prominent therapeutic class. In the course of those investigations, radiolabeled kinase inhibitors for positron emission tomography (PET)
[...] Read more.
Over the last 20 years, intensive investigation and multiple clinical successes targeting protein kinases, mostly for cancer treatment, have identified small molecule kinase inhibitors as a prominent therapeutic class. In the course of those investigations, radiolabeled kinase inhibitors for positron emission tomography (PET) imaging have been synthesized and evaluated as diagnostic imaging probes for cancer characterization. Given that inhibitor coverage of the kinome is continuously expanding, in vivo PET imaging will likely find increasing applications for therapy monitoring and receptor density studies both in- and outside of oncological conditions. Early investigated radiolabeled inhibitors, which are mostly based on clinically approved tyrosine kinase inhibitor (TKI) isotopologues, have now entered clinical trials. Novel radioligands for cancer and PET neuroimaging originating from novel but relevant target kinases are currently being explored in preclinical studies. This article reviews the literature involving radiotracer design, radiochemistry approaches, biological tracer evaluation and nuclear imaging results of radiolabeled kinase inhibitors for PET reported between 2010 and mid-2015. Aspects regarding the usefulness of pursuing selective vs. promiscuous inhibitor scaffolds and the inherent challenges associated with intracellular enzyme imaging will be discussed. Full article
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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