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The Kinase Inhibitors in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 13933

Special Issue Editors

Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
Interests: insulin action; tyrosine kinases; serum and glucorticoid regulated kinase (Sgk); genetics; apoptosis; cancer
Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Interests: electrolyte transporters; serum glucocorticoid induced kinase (SGK); polycystic kidney disease; transient receptor potential vanilloid 4 (TRPV4)

Special Issue Information

Recent achievements in the field of genomic and transcriptomic analyses have uncovered the molecular and genetic mechanisms underlying many genetic diseases. Some of the mutations that are responsible for inherited diseases result in the activation of serine/threonine and/or tyrosine kinases.  For instance, PI3K and mTOR are involved in rare genetically defined overgrowth syndromes and mTORopathies including tuberous sclerosis. Loss of function mutations in the JAK/STAT pathway may be responsible for human immunodeficiency syndromes; alternatively, the gain of function mutations in this pathway has been linked to systemic autoimmunity, polycythemia vera, leukemias, and lymphomas.  Hyperphosphorylation of TAU protein, a feature of Alzheimer's disease, can be attributed to the activity of different kinases, including GSK3, Fyn kinase, or Sgk1.

Finally, loss of function mutations in the genes coding for a group of ciliary proteins, including TMEM67, that regulate the switching from canonical to non-canonical Wnt signaling, may lead to canonical Wnt/beta catenin-dependent overexpression of the kinases responsible for the over-proliferation and dis-regulation of development in the organs affected in ciliopathies.

Taken together, these and other observations suggest the role of kinase inhibitors in the treatment of several human genetic diseases. The use of these kinase inhibitors is, in most cases, still experimental, nevertheless, clinical studies with already available inhibitors, as well as preclinical studies in animal models with novel molecules, may add important tools to the treatment of these rare and devastating diseases.  

We plan to collect contributions that can shed light on important aspects related to the development of kinase inhibitors and to the application of these compounds in selected inherited human diseases.

Prof. Dr. Nicola Perrotti
Prof. Dr. Bonnie Blazer Yost
Guest Editors

Manuscript Submission Information

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Keywords

  • serine and threonine kinases
  • tyrosine kinase
  • MTOR
  • PI3K
  • Sgk1
  • tuberous sclerosis
  • Alzheimer’s disease
  • ciliopathy

Published Papers (6 papers)

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Research

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25 pages, 3604 KiB  
Article
Discovery of New Quinoline-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity
by Hyun Ji Kim, Jung Woo Park, Sangjae Seo, Kwang-Hwi Cho, Mohammed M. Alanazi, Eun-Kyoung Bang, Gyochang Keum and Ashraf K. El-Damasy
Int. J. Mol. Sci. 2023, 24(4), 3216; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043216 - 06 Feb 2023
Cited by 2 | Viewed by 1562
Abstract
The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously [...] Read more.
The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously reported 2-anilinoquinoline-diarylamides conjugate VII as a B-RAFV600E/C-RAF inhibitor. Considering the incorporation of a methylene bridge between the terminal phenyl and cyclic diamine, focused quinoline-based arylamides have been tailored, synthesized, and biologically evaluated. Among them, the 5/6-hydroxyquinolines 17b and 18a stood out as the most potent members, with IC50 values of 0.128 µM, 0.114 µM against B-RAFV600E, and 0.0653 µM, 0.0676 µM against C-RAF. Most importantly, 17b elicited remarkable inhibitory potency against the clinically resistant B-RAFV600K mutant with an IC50 value of 0.0616 µM. The putative binding mode of 17b and 18a were studied by molecular docking and molecular dynamics (MD). Moreover, the antiproliferative activity of all target compounds has been examined over a panel of NCI-60 human cancer cell lines. In agreement with cell-free assays, the designed compounds exerted superior anticancer impact over the lead quinoline VII against all cell lines at a 10 µM dose. Notably, both 17b and 18b showed highly potent antiproliferative activity against melanoma cell lines with growth percent under −90% (SK-MEL-29, SK-MEL-5, and UACC-62) at a single dose, while 17b maintained potency with GI50 values of 1.60–1.89 µM against melanoma cell lines. Taken together, 17b, a promising B-RAFV600E/V600K and C-RAF kinase inhibitor, may serve as a valuable candidate in the arsenal of anticancer chemotherapeutics. Full article
(This article belongs to the Special Issue The Kinase Inhibitors in Human Diseases)
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17 pages, 3640 KiB  
Article
A Real-Time, Plate-Based BRET Assay for Detection of cGMP in Primary Cells
by Adam L. Valkovic, Martina Kocan, Brad Hoare, Sarah Marshall, Daniel J. Scott and Ross A. D. Bathgate
Int. J. Mol. Sci. 2022, 23(3), 1908; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031908 - 08 Feb 2022
Cited by 2 | Viewed by 2584
Abstract
Cyclic guanosine monophosphate (cGMP) is a second messenger involved in the regulation of numerous physiological processes. The modulation of cGMP is important in many diseases, but reliably assaying cGMP in live cells in a plate-based format with temporal resolution is challenging. The Förster/fluorescence [...] Read more.
Cyclic guanosine monophosphate (cGMP) is a second messenger involved in the regulation of numerous physiological processes. The modulation of cGMP is important in many diseases, but reliably assaying cGMP in live cells in a plate-based format with temporal resolution is challenging. The Förster/fluorescence resonance energy transfer (FRET)-based biosensor cGES-DE5 has a high temporal resolution and high selectivity for cGMP over cAMP, so we converted it to use bioluminescence resonance energy transfer (BRET), which is more compatible with plate-based assays. This BRET variant, called CYGYEL (cyclic GMP sensor using YFP-PDE5-Rluc8), was cloned into a lentiviral vector for use across different mammalian cell types. CYGYEL was characterised in HEK293T cells using the nitric oxide donor diethylamine NONOate (DEA), where it was shown to be dynamic, reversible, and able to detect cGMP with or without the use of phosphodiesterase inhibitors. In human primary vascular endothelial and smooth muscle cells, CYGYEL successfully detected cGMP mediated through either soluble or particulate guanylate cyclase using DEA or C-type natriuretic peptide, respectively. Notably, CYGYEL detected differences in kinetics and strength of signal both between ligands and between cell types. CYGYEL remained selective for cGMP over cAMP, but this selectivity was reduced compared to cGES-DE5. CYGYEL streamlines the process of cGMP detection in plate-based assays and can be used to detect cGMP activity across a range of cell types. Full article
(This article belongs to the Special Issue The Kinase Inhibitors in Human Diseases)
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Review

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13 pages, 1581 KiB  
Review
Consideration of Kinase Inhibitors for the Treatment of Hydrocephalus
by Bonnie L. Blazer-Yost
Int. J. Mol. Sci. 2023, 24(7), 6673; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076673 - 03 Apr 2023
Cited by 1 | Viewed by 1303
Abstract
Hydrocephalus is a devastating condition characterized by excess cerebrospinal fluid (CSF) in the brain. Currently, the only effective treatment is surgical intervention, usually involving shunt placement, a procedure prone to malfunction, blockage, and infection that requires additional, often repetitive, surgeries. There are no [...] Read more.
Hydrocephalus is a devastating condition characterized by excess cerebrospinal fluid (CSF) in the brain. Currently, the only effective treatment is surgical intervention, usually involving shunt placement, a procedure prone to malfunction, blockage, and infection that requires additional, often repetitive, surgeries. There are no long-term pharmaceutical treatments for hydrocephalus. To initiate an intelligent drug design, it is necessary to understand the biochemical changes underlying the pathology of this chronic condition. One potential commonality in the various forms of hydrocephalus is an imbalance in fluid–electrolyte homeostasis. The choroid plexus, a complex tissue found in the brain ventricles, is one of the most secretory tissues in the body, producing approximately 500 mL of CSF per day in an adult human. In this manuscript, two key transport proteins of the choroid plexus epithelial cells, transient receptor potential vanilloid 4 and sodium, potassium, 2 chloride co-transporter 1, will be considered. Both appear to play key roles in CSF production, and their inhibition or genetic manipulation has been shown to affect CSF volume. As with most transporters, these proteins are regulated by kinases. Therefore, specific kinase inhibitors are also potential targets for the development of pharmaceuticals to treat hydrocephalus. Full article
(This article belongs to the Special Issue The Kinase Inhibitors in Human Diseases)
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21 pages, 1601 KiB  
Review
Kinase Inhibitors in Genetic Diseases
by Lucia D’Antona, Rosario Amato, Carolina Brescia, Valentina Rocca, Emma Colao, Rodolfo Iuliano, Bonnie L. Blazer-Yost and Nicola Perrotti
Int. J. Mol. Sci. 2023, 24(6), 5276; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065276 - 09 Mar 2023
Viewed by 1594
Abstract
Over the years, several studies have shown that kinase-regulated signaling pathways are involved in the development of rare genetic diseases. The study of the mechanisms underlying the onset of these diseases has opened a possible way for the development of targeted therapies using [...] Read more.
Over the years, several studies have shown that kinase-regulated signaling pathways are involved in the development of rare genetic diseases. The study of the mechanisms underlying the onset of these diseases has opened a possible way for the development of targeted therapies using particular kinase inhibitors. Some of these are currently used to treat other diseases, such as cancer. This review aims to describe the possibilities of using kinase inhibitors in genetic pathologies such as tuberous sclerosis, RASopathies, and ciliopathies, describing the various pathways involved and the possible targets already identified or currently under study. Full article
(This article belongs to the Special Issue The Kinase Inhibitors in Human Diseases)
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22 pages, 5557 KiB  
Review
The Development of FAK Inhibitors: A Five-Year Update
by Andrea Spallarossa, Bruno Tasso, Eleonora Russo, Carla Villa and Chiara Brullo
Int. J. Mol. Sci. 2022, 23(12), 6381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126381 - 07 Jun 2022
Cited by 16 | Viewed by 2976
Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on [...] Read more.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view. Full article
(This article belongs to the Special Issue The Kinase Inhibitors in Human Diseases)
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19 pages, 2527 KiB  
Review
The Role of SUMO E3 Ligases in Signaling Pathway of Cancer Cells
by Xiaoxia Shi, Yixin Du, Shujing Li and Huijian Wu
Int. J. Mol. Sci. 2022, 23(7), 3639; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073639 - 26 Mar 2022
Cited by 4 | Viewed by 3137
Abstract
Small ubiquitin-like modifier (SUMO)ylation is a reversible post-translational modification that plays a crucial role in numerous aspects of cell physiology, including cell cycle regulation, DNA damage repair, and protein trafficking and turnover, which are of importance for cell homeostasis. Mechanistically, SUMOylation is a [...] Read more.
Small ubiquitin-like modifier (SUMO)ylation is a reversible post-translational modification that plays a crucial role in numerous aspects of cell physiology, including cell cycle regulation, DNA damage repair, and protein trafficking and turnover, which are of importance for cell homeostasis. Mechanistically, SUMOylation is a sequential multi-enzymatic process where SUMO E3 ligases recruit substrates and accelerate the transfer of SUMO onto targets, modulating their interactions, localization, activity, or stability. Accumulating evidence highlights the critical role of dysregulated SUMO E3 ligases in processes associated with the occurrence and development of cancers. In the present review, we summarize the SUMO E3 ligases, in particular, the novel ones recently identified, and discuss their regulatory roles in cancer pathogenesis. Full article
(This article belongs to the Special Issue The Kinase Inhibitors in Human Diseases)
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