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Special Issue "Design and Study of Kinase Inhibitors"

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

Deadline for manuscript submissions: closed (31 July 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Philippe Belmont

School of Pharmacy, University Paris Descartes, UMR CNRS 8638, case 24. 4, avenue de l’Observatoire, 75006 Paris, France
E-Mail
Interests: heterocyclic synthesis; nitrogen-containing heterocycles; methodologies using organic or organometallic reagents; organometallic catalysis; cyclo-isomerization reactions; cyclo-functionalization reactions; benzannulation; aminobenzannulation; pi-acid metal catalysis; silver chemistry; gold chemistry; cobalt chemistry; Pauson-Khand reaction; bioactive compounds; alkaloids; kinases inhibition

Special Issue Information

Dear Colleagues,

In recent years, the design and study of kinase inhibitors has become an important field of interest. The arrival of imatinib (Glivec®, Novartis) on the market in the early 2000s opened the way for targeted therapies with heterocyclic molecules. Meanwhile, heterocyclic chemistry has received increasing attention in organic and organometallic methodologies. The green chemistry development brought the community access to heterocycles through new, efficient, and eco-friendly methodologies, including novel chemical conditions (e.g., metal-catalyzed or metal-free) and the use of new reaction conditions (e.g., microwave, solvent-free). Thanks to co-crystallization data (when possible) and molecular modeling studies (including docking), the link between heterocycle synthesis and their kinases’ inhibitory properties (i.e., the structure-activity relationships) has been further elucidated and is nowadays increasingly predictable.

Therefore, the Special Issue’s scope, which concerns the “design and study of kinase inhibitors”, is broad. Possible topics may concern original access to various heterocyclic cores (through creative methodological developments) and close collaborations with either biologists/crystallographers or molecular modeling partners that empower inhibitor development and the hit to lead maturation.

Prof. Dr. Philippe Belmont
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. 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).


Keywords

  • heterocycles
  • kinase inhibition
  • signal transduction study
  • organic synthesis
  • organometallic catalysis
  • molecular modeling

Published Papers (15 papers)

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Research

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Open AccessArticle Stability of the Human Hsp90-p50Cdc37 Chaperone Complex against Nucleotides and Hsp90 Inhibitors, and the Influence of Phosphorylation by Casein Kinase 2
Molecules 2015, 20(1), 1643-1660; doi:10.3390/molecules20011643
Received: 1 December 2014 / Accepted: 12 January 2015 / Published: 19 January 2015
Cited by 2 | PDF Full-text (2579 KB) | HTML Full-text | XML Full-text
Abstract
The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein–protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases
[...] Read more.
The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein–protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2) did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM), while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessArticle Identification and Characterization of Amlexanox as a G Protein-Coupled Receptor Kinase 5 Inhibitor
Molecules 2014, 19(10), 16937-16949; doi:10.3390/molecules191016937
Received: 8 September 2014 / Revised: 11 October 2014 / Accepted: 14 October 2014 / Published: 22 October 2014
Cited by 8 | PDF Full-text (1098 KB) | HTML Full-text | XML Full-text
Abstract
G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a target
[...] Read more.
G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a target for the treatment of cardiac hypertrophy, and the mechanism of action of reported compounds is unknown. To identify novel scaffolds that selectively inhibit GRK5, a differential scanning fluorometry screen was used to probe a library of 4480 compounds. The best hit was amlexanox, an FDA-approved anti-inflammatory, anti-allergic immunomodulator. The crystal structure of amlexanox in complex with GRK1 demonstrates that its tricyclic aromatic ring system forms ATP-like interactions with the hinge of the kinase domain, which is likely similar to how this drug binds to IκB kinase ε (IKKε), another kinase known to be inhibited by this compound. Amlexanox was also able to inhibit myocyte enhancer factor 2 transcriptional activity in neonatal rat ventricular myocytes in a manner consistent with GRK5 inhibition. The GRK1 amlexanox structure thus serves as a springboard for the rational design of inhibitors with improved potency and selectivity for GRK5 and IKKε. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
Open AccessArticle Structural Elucidation of the DFG-Asp in and DFG-Asp out States of TAM Kinases and Insight into the Selectivity of Their Inhibitors
Molecules 2014, 19(10), 16223-16239; doi:10.3390/molecules191016223
Received: 31 July 2014 / Revised: 24 September 2014 / Accepted: 26 September 2014 / Published: 10 October 2014
Cited by 3 | PDF Full-text (2603 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members
[...] Read more.
Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessArticle Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I
Molecules 2014, 19(10), 15546-15571; doi:10.3390/molecules191015546
Received: 29 July 2014 / Revised: 19 September 2014 / Accepted: 22 September 2014 / Published: 29 September 2014
Cited by 9 | PDF Full-text (960 KB) | HTML Full-text | XML Full-text
Abstract
The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16)
[...] Read more.
The convenient synthesis of a library of novel 6,6,5-tricyclic thiazolo[5,4-f] quinazolines (forty molecules) was achieved mainly under microwave irradiation. Dimroth rearrangement and 4,5-dichloro-1,2,3,-dithiazolium chloride (Appel salt) chemistry were associated for the synthesis of a novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (16) a versatile molecular platform for the synthesis of various bioactive derivatives. Kinase inhibition of the final compounds was evaluated on a panel of four Ser/Thr kinases (DYRK1A, CDK5, CK1 and GSK3) chosen for their strong implications in various regulation processes, especially Alzheimer’s disease (AD). In view of the results of this preliminary screening, thiazolo[5,4-f]quinazoline scaffolds constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. Among the compounds of this novel chemolibrary, 7i, 8i and 9i inhibited DYRK1A with IC50 values ranging in the double-digit nanomolar range (40, 47 and 50 nM, respectively). Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessArticle Design and Synthesis of C-Terminal Modified Cyclic Peptides as VEGFR1 Antagonists
Molecules 2014, 19(10), 15391-15407; doi:10.3390/molecules191015391
Received: 7 August 2014 / Revised: 12 September 2014 / Accepted: 17 September 2014 / Published: 26 September 2014
PDF Full-text (1728 KB) | HTML Full-text | XML Full-text
Abstract
Previously designed cyclic peptide antagonist c[YYDEGLEE]-NH2 disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). It represents a promising tool in the fight against cancer and age-related macular degeneration. We described in this paper the optimization of the
[...] Read more.
Previously designed cyclic peptide antagonist c[YYDEGLEE]-NH2 disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). It represents a promising tool in the fight against cancer and age-related macular degeneration. We described in this paper the optimization of the lead peptide by C-terminal modification. A new strategy for the synthesis of cyclic peptides is developed, improving the cyclisation efficiency. At 100 µM, several new peptides with an aromatic group flexibly linked at C-terminal end showed significantly increased receptor binding affinities in competition ELISA test. The most active peptide carrying a coumarin group may be a useful tool in anti-angiogenic biological studies. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
Open AccessArticle Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II
Molecules 2014, 19(10), 15411-15439; doi:10.3390/molecules191015411
Received: 7 August 2014 / Revised: 15 September 2014 / Accepted: 16 September 2014 / Published: 26 September 2014
Cited by 10 | PDF Full-text (940 KB) | HTML Full-text | XML Full-text
Abstract
The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase
[...] Read more.
The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessArticle Several Human Cyclin-Dependent Kinase Inhibitors, Structurally Related to Roscovitine, As New Anti-Malarial Agents
Molecules 2014, 19(9), 15237-15257; doi:10.3390/molecules190915237
Received: 31 July 2014 / Revised: 8 September 2014 / Accepted: 11 September 2014 / Published: 23 September 2014
Cited by 7 | PDF Full-text (877 KB) | HTML Full-text | XML Full-text
Abstract
In Africa, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs.
[...] Read more.
In Africa, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs. Among newly proposed anti-malaria targets, are the P. falciparum cyclin-dependent kinases (PfCDKs). There are involved in different stages of the protozoan growth and development but share high sequence homology with human cyclin-dependent kinases (CDKs). We previously reported the synthesis of CDKs inhibitors that are structurally-related to (R)-roscovitine, a 2,6,9-trisubstituted purine, and they showed activity against neuronal diseases and cancers. In this report, we describe the synthesis and the characterization of new CDK inhibitors, active in reducing the in vitro growth of P. falciparum (3D7 and 7G8 strains). Six compounds are more potent inhibitors than roscovitine, and three exhibited IC50 values close to 1 µM for both 3D7 and 7G8 strains. Although, such molecules do inhibit P. falciparum growth, they require further studies to improve their selectivity for PfCDKs. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessArticle Cytotoxic Activity of 3,6-Dihydroxyflavone in Human Cervical Cancer Cells and Its Therapeutic Effect on c-Jun N-Terminal Kinase Inhibition
Molecules 2014, 19(9), 13200-13211; doi:10.3390/molecules190913200
Received: 15 July 2014 / Revised: 18 August 2014 / Accepted: 22 August 2014 / Published: 27 August 2014
Cited by 6 | PDF Full-text (1330 KB) | HTML Full-text | XML Full-text
Abstract
Previously we have shown that 3,6-dihydroxyflavone (3,6-DHF) is a potent agonist of the human peroxisome proliferator-activated receptor (hPPAR) with cytotoxic effects on human cervical cancer cells. To date, the mechanisms by which 3,6-DHF exerts its antitumor effects on cervical cells have not been
[...] Read more.
Previously we have shown that 3,6-dihydroxyflavone (3,6-DHF) is a potent agonist of the human peroxisome proliferator-activated receptor (hPPAR) with cytotoxic effects on human cervical cancer cells. To date, the mechanisms by which 3,6-DHF exerts its antitumor effects on cervical cells have not been clearly defined. Here, we demonstrated that 3,6-DHF exhibits a novel antitumor activity against HeLa cells with IC50 values of 25 μM and 9.8 μM after 24 h and 48 h, respectively. We also showed that the anticancer effects of 3,6-DHF are mediated via the toll-like receptor (TLR) 4/CD14, p38 mitogen-activated protein kinase (MAPK), Jun-N terminal kinase (JNK), extracellular-signaling regulated kinase (ERK), and cyclooxygenase (COX)-2 pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. We found that 3,6-DHF showed a similar IC50 (113 nM) value to that of the JNK inhibitor, SP600125 (IC50 = 118 nM) in a JNK1 kinase assay. Binding studies revealed that 3,6-DHF had a strong binding affinity to JNK1 (1.996 × 105 M1) and that the 6-OH and the carbonyl oxygen of the C ring of 3,6-DHF participated in hydrogen bonding interactions with the carbonyl oxygen and the amide proton of Met111, respectively. Therefore, 3,6-DHF may be a candidate inhibitor of JNKs, with potent anticancer effects. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessCommunication Using MUSIC and CC(CO)NH for Backbone Assignment of Two Medium-Sized Proteins Not Fully Accessible to Standard 3D NMR
Molecules 2014, 19(7), 8890-8903; doi:10.3390/molecules19078890
Received: 5 May 2014 / Revised: 5 June 2014 / Accepted: 12 June 2014 / Published: 26 June 2014
Cited by 1 | PDF Full-text (306 KB) | HTML Full-text | XML Full-text
Abstract
The backbone assignment of medium-sized proteins is rarely as straightforward as that of small proteins, and thus often requires creative solutions. Here, we describe the application of a combination of standard 3D heteronuclear methods with CC(CO)NH and a variety of MUltiplicity Selective In-phase
[...] Read more.
The backbone assignment of medium-sized proteins is rarely as straightforward as that of small proteins, and thus often requires creative solutions. Here, we describe the application of a combination of standard 3D heteronuclear methods with CC(CO)NH and a variety of MUltiplicity Selective In-phase Coherence transfer (MUSIC) experiments. Both CC(CO)NH and MUSIC are, in theory, very powerful methods for the backbone assignment of proteins. Due to low sensitivity, their use has usually been linked to small proteins only. However, we found that combining CC(CO)NH and MUSIC experiments simplified the assignment of two challenging medium-sized proteins of 13 and 19.5 kDa, respectively. These methods are to some extent complementary to each other: CC(CO)NH acquired with a long isotropic mixing time can identify amino acids with large aliphatic side chains. Whereas the most sensitive MUSIC experiments identify amino acid types that cannot be detected by CC(CO)NH, comprising the residues with acid and amide groups, and aromatic rings in their side chains. Together these methods provide a means of identifying the majority of peaks in the 2D 15N HSQC spectrum which simplifies the backbone assignment work even for proteins, e.g., small kinases, whose standard spectra resulted in little spectral resolution and low signal intensities. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)

Review

Jump to: Research

Open AccessReview The Azaindole Framework in the Design of Kinase Inhibitors
Molecules 2014, 19(12), 19935-19979; doi:10.3390/molecules191219935
Received: 16 October 2014 / Revised: 10 November 2014 / Accepted: 18 November 2014 / Published: 28 November 2014
Cited by 19 | PDF Full-text (1943 KB) | HTML Full-text | XML Full-text
Abstract
This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug
[...] Read more.
This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessReview Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms
Molecules 2014, 19(11), 18414-18447; doi:10.3390/molecules191118414
Received: 15 August 2014 / Revised: 28 October 2014 / Accepted: 2 November 2014 / Published: 12 November 2014
Cited by 13 | PDF Full-text (777 KB) | HTML Full-text | XML Full-text
Abstract
The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of
[...] Read more.
The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of several human malignancies, including acute myeloid leukemia (AML); and CDC25 inhibition is therefore considered as a possible anticancer strategy. Firstly, upregulation of CDC25A can enhance cell proliferation and the expression seems to be controlled through PI3K-Akt-mTOR signaling, a pathway possibly mediating chemoresistance in human AML. Loss of CDC25A is also important for the cell cycle arrest caused by differentiation induction of malignant hematopoietic cells. Secondly, high CDC25B expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors in primary human AML cells, and inhibition of this isoform seems to reduce AML cell line proliferation through effects on NFκB and p300. Finally, CDC25C seems important for the phenotype of AML cells at least for a subset of patients. Many of the identified CDC25 inhibitors show cross-reactivity among the three CDC25 isoforms. Thus, by using such cross-reactive inhibitors it may become possible to inhibit several molecular events in the regulation of cell cycle progression and even cytoplasmic signaling, including activation of several CDKs, through the use of a single drug. Such combined strategies will probably be an advantage in human cancer treatment. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
Open AccessReview Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer
Molecules 2014, 19(9), 15196-15212; doi:10.3390/molecules190915196
Received: 6 August 2014 / Revised: 8 September 2014 / Accepted: 10 September 2014 / Published: 23 September 2014
Cited by 11 | PDF Full-text (756 KB) | HTML Full-text | XML Full-text
Abstract
The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of
[...] Read more.
The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
Open AccessReview Inhibition of the PI3K/Akt/mTOR Signaling Pathway in Diffuse Large B-Cell Lymphoma: Current Knowledge and Clinical Significance
Molecules 2014, 19(9), 14304-14315; doi:10.3390/molecules190914304
Received: 22 July 2014 / Revised: 3 September 2014 / Accepted: 9 September 2014 / Published: 11 September 2014
Cited by 13 | PDF Full-text (1133 KB) | HTML Full-text | XML Full-text
Abstract
Diffuse large B-cell lymphoma (DLBCL) is one of the most common non-Hodgkin lymphomas in adults. The disease is very heterogeneous in its presentation, that is DLBCL patients may differ from each other not only in regard to histology of tissue infiltration, clinical course
[...] Read more.
Diffuse large B-cell lymphoma (DLBCL) is one of the most common non-Hodgkin lymphomas in adults. The disease is very heterogeneous in its presentation, that is DLBCL patients may differ from each other not only in regard to histology of tissue infiltration, clinical course or response to treatment, but also in respect to diversity in gene expression profiling. A growing body of knowledge on the biology of DLBCL, including abnormalities in intracellular signaling, has allowed the development of new treatment strategies, specifically directed against lymphoma cells. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in controlling proliferation and survival of tumor cells in various types of malignancies, including DLBCL, and therefore it may be a promising target for therapeutic intervention. Currently, novel anticancer drugs are undergoing assessment in different phases of clinical trials in aggressive lymphomas, with promising outcomes. In this review we present a state of art review on various classes of small molecule inhibitors selectively involving PI3K/Akt/mTOR pathway and their clinical potential in this disease. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
Open AccessReview Cyclin-Dependent Kinase Inhibitors as Marketed Anticancer Drugs: Where Are We Now? A Short Survey
Molecules 2014, 19(9), 14366-14382; doi:10.3390/molecules190914366
Received: 25 July 2014 / Revised: 26 August 2014 / Accepted: 28 August 2014 / Published: 11 September 2014
Cited by 20 | PDF Full-text (938 KB) | HTML Full-text | XML Full-text
Abstract
In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been
[...] Read more.
In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been thoroughly studied, none of the compounds commercialized since then target cyclin-dependent kinases (CDKs). Following a recent and detailed review on the subject by Galons et al., we concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors. CDK inhibition profiles and clinical development stages are reported for the 14 compounds under clinical evaluation. Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors are briefly described, along with their limitations. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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Open AccessReview Tyrosine Kinase Inhibitors as Reversal Agents for ABC Transporter Mediated Drug Resistance
Molecules 2014, 19(9), 13848-13877; doi:10.3390/molecules190913848
Received: 31 July 2014 / Revised: 25 August 2014 / Accepted: 29 August 2014 / Published: 4 September 2014
Cited by 23 | PDF Full-text (1141 KB) | HTML Full-text | XML Full-text
Abstract
Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with
[...] Read more.
Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with the activity of deregulated kinases. These TKIs are remarkably effective in the treatment of various human cancers including head and neck, gastric, prostate and breast cancer and several types of leukemia. However, these TKIs are transported out of the cell by ATP-binding cassette (ABC) transporters, resulting in development of a characteristic drug resistance phenotype in cancer patients. Interestingly, some of these TKIs also inhibit the ABC transporter mediated multi drug resistance (MDR) thereby; enhancing the efficacy of conventional chemotherapeutic drugs. This review discusses the clinically relevant TKIs and their interaction with ABC drug transporters in modulating MDR. Full article
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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