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Kinases and Phosphatases
Special Issues
Human Protein Kinases: Development of Small-Molecule Therapies
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Human Protein Kinases: Development of Small-Molecule Therapies

A special issue of Kinases and Phosphatases (ISSN 2813-3757).

Deadline for manuscript submissions: 30 December 2024 | Viewed by 18479

Special Issue Editor

Dr. Alison D. Axtman

E-Mail Website
Guest Editor
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Interests: synthesis of small molecules

Special Issue Information

Dear Colleagues,

Protein kinases play essential roles in the human body. Changes in kinase expression and/or function due to mutations, overexpression, or loss of function have been linked with diverse diseases. Accordingly, the modulation of kinases is viewed as a therapeutic strategy. The development of small-molecule kinase inhibitors has resulted in 71 FDA-approved drugs. Kinase activation is another approach that may have utility in cases where loss of function propagates disease. Finally, the degradation of kinases is an alternative strategy that is quickly gaining traction in diseases where kinase overexpression drives pathology. As kinases are amongst the most tractable proteins in the human proteome, the design and development of small molecules targeting them is an attractive avenue to modulate their function in human disorders.

This Special Issue, “Human Protein Kinases: Development of Small-Molecule Therapies”, welcomes submissions of original research articles and reviews on the development and use of kinase-targeting small molecules for a therapeutic endpoint. Research can be exclusively pre-clinical, but must advance as far as cell-based studies. Preference will be given to studies dedicated to human kinases for which several small-molecule modulators have not already been described and/or novel modalities (activation or degradation) for targeting kinases. The application of small molecules to modify kinase function for non-oncological indications is encouraged.

Dr. Alison D. Axtman
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 submissions that pass pre-check are 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. Kinases and Phosphatases is an international peer-reviewed open access quarterly 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 1000 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

  • human kinase;
  • kinase inhibitor;
  • PROTAC;
  • kinase activation;
  • human disease;
  • small molecule;
  • understudied

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Published Papers (6 papers)

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Review

13 pages, 639 KiB  
Review
Kinases Inhibitors as New Therapeutic Opportunities in Cutaneous T-Cell Lymphoma
by Sara Valero-Diaz, Camilla Amato and Berta Casar
Kinases Phosphatases 2024, 2(3), 255-267; https://doi.org/10.3390/kinasesphosphatases2030016 - 28 Aug 2024
Viewed by 911
Abstract
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the [...] Read more.
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas. Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
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13 pages, 1321 KiB  
Review
Exogenous and Endogenous Molecules Potentially Proficient to Modulate Mitophagy in Cardiac Disorders
by Moeka Nakashima, Naoko Suga and Satoru Matsuda
Kinases Phosphatases 2024, 2(2), 166-178; https://doi.org/10.3390/kinasesphosphatases2020010 - 23 May 2024
Viewed by 1481
Abstract
It has been proposed that procedures which upregulate mitochondrial biogenesis and autophagy by replacing damaged mitochondria with healthy ones may prevent the development of several heart diseases. A member of serine and threonine kinases, adenosine monophosphate-activated protein kinase (AMPK), could play essential roles [...] Read more.
It has been proposed that procedures which upregulate mitochondrial biogenesis and autophagy by replacing damaged mitochondria with healthy ones may prevent the development of several heart diseases. A member of serine and threonine kinases, adenosine monophosphate-activated protein kinase (AMPK), could play essential roles in the autophagy and/or mitophagy. AMPK is widely distributed in various cells, which might play diverse regulatory roles in different tissues and/or organs. In fact, changes in the kinase function of AMPK due to alteration of activity have been linked with diverse pathologies including cardiac disorders. AMPK can regulate mitochondrial biogenesis via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) signaling and also improve oxidative mitochondrial metabolism through inhibition of mechanistic/mammalian target of rapamycin (mTOR) pathway, which may also modulate the autophagy/mitophagy through autophagy activating kinase 1 (ULK1) and/or transforming growth factor beta (TGF-β) signaling. Therefore, the modulation of AMPK in autophagy/mitophagy pathway might probably be thought as a therapeutic tactic for several cardiac disorders. As kinases are amongst the most controllable proteins, in general, the design of small molecules targeting kinases might be an eye-catching avenue to modulate cardiac function. Some analyses of the molecular biology underlying mitophagy suggest that nutraceuticals and/or drugs including specific AMPK modulator as well as physical exercise and/or dietary restriction that could modulate AMPK may be useful against several heart diseases. These observations may virtually be limited to preclinical studies. Come to think of these, however, it is speculated that some nutraceutical regimens might have positive potential for managing some of cardiac disorders. Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
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19 pages, 4136 KiB  
Review
The Yin and Yang of IκB Kinases in Cancer
by Abdalla M. Abdrabou
Kinases Phosphatases 2024, 2(1), 9-27; https://doi.org/10.3390/kinasesphosphatases2010002 - 31 Dec 2023
Cited by 2 | Viewed by 2025
Abstract
IκB kinases (IKKs), specifically IKKα and IKKβ, have long been recognized for their pivotal role in the NF-κB pathway, orchestrating immune and inflammatory responses. However, recent years have unveiled their dual role in cancer, where they can act as both promoters and suppressors [...] Read more.
IκB kinases (IKKs), specifically IKKα and IKKβ, have long been recognized for their pivotal role in the NF-κB pathway, orchestrating immune and inflammatory responses. However, recent years have unveiled their dual role in cancer, where they can act as both promoters and suppressors of tumorigenesis. In addition, the interplay with pathways such as the MAPK and PI3K pathways underscores the complexity of IKK regulation and its multifaceted role in both inflammation and cancer. By exploring the molecular underpinnings of these processes, we can better comprehend the complex interplay between IKKs, tumor development, immune responses, and the development of more effective therapeutics. Ultimately, this review explores the dual role of IκB kinases in cancer, focusing on the impact of phosphorylation events and crosstalk with other signaling pathways, shedding light on their intricate regulation and multifaceted functions in both inflammation and cancer. Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
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23 pages, 5804 KiB  
Review
Interaction Networks Explain Holoenzyme Allostery in Protein Kinase A
by Colin L. Welsh, Abigail E. Conklin and Lalima K. Madan
Kinases Phosphatases 2023, 1(4), 265-287; https://doi.org/10.3390/kinasesphosphatases1040016 - 31 Oct 2023
Viewed by 2168
Abstract
Protein kinase A (PKA) signaling exemplifies phosphorylation-based signaling as we understand it today. Its catalytic-subunit structure and dynamics continue to advance our understanding of kinase mechanics as the first protein kinase catalytic domain to be identified, sequenced, cloned, and structurally detailed. The PKA [...] Read more.
Protein kinase A (PKA) signaling exemplifies phosphorylation-based signaling as we understand it today. Its catalytic-subunit structure and dynamics continue to advance our understanding of kinase mechanics as the first protein kinase catalytic domain to be identified, sequenced, cloned, and structurally detailed. The PKA holoenzyme elaborates on the role of its regulatory subunits and maintains our understanding of cAMP-dependent cellular signaling. The activation of PKA holoenzymes by cAMP is an example of specialized protein allostery, emphasizing the relevance of protein binding interfaces, unstructured regions, isoform diversity, and dynamics-based allostery. This review provides the most up-to-date overview of PKA structure and function, including a description of the catalytic and regulatory subunits’ structures. In addition, the structure, activation, and allostery of holoenzymes are covered. Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
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25 pages, 3719 KiB  
Review
Therapeutic Perspectives on ROCK Inhibition for Cerebral Cavernous Malformations
by Tadeu L. Montagnoli, Daniela R. de Oliveira and Carlos A. Manssour Fraga
Kinases Phosphatases 2023, 1(1), 72-96; https://doi.org/10.3390/kinasesphosphatases1010006 - 23 Feb 2023
Cited by 3 | Viewed by 4216
Abstract
Cerebral cavernous malformations (CCM) are developmental venous dysplasias which present as abnormally dilated blood vessels occurring mainly in the brain. Alterations in vascular biology originate from somatic mutations in genes regulating angiogenesis and endothelial-to-mesenchymal transition. Vascular lesions may occur at any time and [...] Read more.
Cerebral cavernous malformations (CCM) are developmental venous dysplasias which present as abnormally dilated blood vessels occurring mainly in the brain. Alterations in vascular biology originate from somatic mutations in genes regulating angiogenesis and endothelial-to-mesenchymal transition. Vascular lesions may occur at any time and develop silently, remaining asymptomatic for years. However, symptomatic disease is often debilitating, and patients are prone to develop drug-resistant epilepsy and hemorrhages. There is no cure, and surgical treatment is recommended only for superficial lesions on cortical areas. The study of lesion biology led to the identification of different pathways related to disease onset and progression, of which RhoA/Rho-associated protein kinase (ROCK) shows activation in different subsets of patients. This work will explore the current knowledge about the involvement of ROCK in the many aspects of CCM disease, including isoform-specific actions, and delineate the recent development of ROCK inhibitors for CNS-targeted diseases. Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
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16 pages, 3385 KiB  
Review
Lyn Kinase Structure, Regulation, and Involvement in Neurodegenerative Diseases: A Mini Review
by Pathum M. Weerawarna and Timothy I. Richardson
Kinases Phosphatases 2023, 1(1), 23-38; https://doi.org/10.3390/kinasesphosphatases1010004 - 23 Jan 2023
Cited by 3 | Viewed by 6533
Abstract
LYN proto-oncogene, Src family tyrosine kinase (Lyn) is a tyrosine kinase that belongs to the Src family (SFK). It is expressed as two isoforms in humans, LynA and LynB. Like other SFKs, Lyn consists of five protein domains, an N-terminal SH4 domain followed [...] Read more.
LYN proto-oncogene, Src family tyrosine kinase (Lyn) is a tyrosine kinase that belongs to the Src family (SFK). It is expressed as two isoforms in humans, LynA and LynB. Like other SFKs, Lyn consists of five protein domains, an N-terminal SH4 domain followed by a unique domain, the SH3 and SH2 domains, and a catalytic SH1 domain. The autophosphorylation of Tyr397 activates the protein, while the phosphorylation of the C-terminal inhibitory Tyr508 by C-terminal Src kinase (Csk) or Csk homologous kinase (Chk) inhibits the catalytic activity. The interaction of the SH2 domain with the phosphorylated Tyr508 stabilizes a compact, self-inhibited state. The interaction of the SH3 domain with a linker between the SH2 and catalytic domains further stabilizes this inactive conformation. The two critical structural features of the catalytic domain are a conserved DFG moiety and the αC helix, which can adopt in or out conformations. In the active state, both the DFG moiety and αC helix adopt in conformations, while in the inactive state, they adopt out conformations. Lyn has well-established functions in various hematopoietic cell types and more recent studies have revealed its roles in non-hematopoietic cells. At the molecular level, these functions are mainly exerted by phosphorylating specific tyrosine residues in immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activator motifs (ITAMs) associated with cell surface receptors. The phosphorylation of ITAMs by Lyn can initiate either activating or inhibitory (ITAMi) cell signaling depending on the receptor, targeting mode (crosslinking or monovalent targeting), and the cellular context. The phosphorylation of ITIMs by Lyn initiates inhibitory cell signaling via the recruitment of phosphatases to the ITIM-bearing receptor. The role of Lyn in cancer and autoimmune diseases has been extensively discussed in the literature. The involvement of Lyn in neurodegenerative diseases has been described more recently and, as such, it is now an emerging target for the treatment of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
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