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Pharmaceuticals
Special Issues
Kinase Inhibitors in Targeted Cancer Therapy
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Special Issue "Kinase Inhibitors in Targeted Cancer Therapy"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 November 2023 | Viewed by 4269

Special Issue Editors

Dr. Anna Carbone

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy
Interests: medicinal chemistry; drug discovery; small molecules; antitumor agents; kinase inhibitors; synthetic lethality
Dr. Valeria Francesconi

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy
Interests: medicinal chemistry; drug discovery; heterocyclic compounds; small molecules; anticancer agents; antiviral agents

Special Issue Information

Dear Colleagues,

The dysregulation of protein kinase activity plays a central role in the pathogenesis of several diseases. Thus, protein kinases have become one of the most important drug targets. They represent one of the largest gene families in eukaryotes, with more than 518 kinases in the human kinome, and are involved in cell division, cell death, transcription, and cell metabolism The success of imatinib, the first oral tyrosine kinase inhibitor approved by the Federal Drug Administration (FDA) in 2001 for chronic myelogenous leukemia, promoted the extensive use of kinase inhibitors (KIs) as anticancer agents.

KIs include small molecules as well as kinase-targeted antibodies and antibody conjugates. There are 62 FDA-approved small molecule kinase inhibitors, and about 180 are in clinical trials so far. However, despite the growing number of inhibitors, there are many limitations in their clinical use, such as the development of resistance and a low efficacy due to the activation of compensatory signaling pathways.

In this Special Issue entitled “Kinase Inhibitors as Targeted Cancer Therapy”, Pharmaceuticals welcomes original research articles and high-quality reviews focused on the investigation of novel small molecule-targeting protein kinases, as well as on structural and functional studies, increasing knowledge around these key enzymes.

Dr. Anna Carbone
Dr. Valeria Francesconi
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 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. Pharmaceuticals 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 2900 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

  • cancer
  • antitumor agents
  • small molecules
  • kinase inhibitors
  • drug design
  • computer-aided drug discovery

Published Papers (3 papers)

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Research

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Article
Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor
by
Claudia Contadini
,
Claudia Cirotti
,
Anna Carbone
,
Mehrdad Norouzi
,
Annarita Cianciusi
,
Emmanuele Crespan
,
Cecilia Perini
,
Giovanni Maga
,
Daniela Barilà
,
Francesca Musumeci
and
Silvia Schenone
Pharmaceuticals 2023, 16(7), 958; https://doi.org/10.3390/ph16070958 - 04 Jul 2023
Viewed by 538
Abstract
Src is a non-receptor tyrosine kinase (TK) whose involvement in cancer, including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a [...] Read more.
Src is a non-receptor tyrosine kinase (TK) whose involvement in cancer, including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388) was identified as the most potent Src inhibitor. Based on the cell-free results, we investigated the effect of SI388 in 2D and 3D GBM cellular models. Interestingly, SI388 significantly inhibits Src kinase, and therefore affects cell viability, tumorigenicity and enhances cancer cell sensitivity to ionizing radiation. Full article
(This article belongs to the Special Issue Kinase Inhibitors in Targeted Cancer Therapy)
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Review

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Review
An Intriguing Purview on the Design of Macrocyclic Inhibitors for Unexplored Protein Kinases through Their Binding Site Comparison
by
Swapnil P. Bhujbal
and
Jung-Mi Hah
Pharmaceuticals 2023, 16(7), 1009; https://doi.org/10.3390/ph16071009 - 17 Jul 2023
Viewed by 517
Abstract
Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival, and other cellular processes, and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to developing new therapeutic agents for [...] Read more.
Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival, and other cellular processes, and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to developing new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding sites provides crucial insights for drug discovery and development. Binding site similarities are helpful in understanding polypharmacology, identifying potential off-targets, and repurposing known drugs. In this review, we focused on comparing the binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of the binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed to date. Our review and analysis of several explored kinases might be useful in targeting new protein kinases for macrocyclic drug discovery. Full article
(This article belongs to the Special Issue Kinase Inhibitors in Targeted Cancer Therapy)
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Review
Structure–Activity Relationship Studies Based on Quinazoline Derivatives as EGFR Kinase Inhibitors (2017–Present)
by
Alexandru Șandor
,
Ioana Ionuț
,
Gabriel Marc
,
Ilioara Oniga
,
Dan Eniu
and
Ovidiu Oniga
Pharmaceuticals 2023, 16(4), 534; https://doi.org/10.3390/ph16040534 - 03 Apr 2023
Cited by 2 | Viewed by 2805
Abstract
The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified as an attractive therapeutic approach and led to the approval of three generations of inhibitors. The [...] Read more.
The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified as an attractive therapeutic approach and led to the approval of three generations of inhibitors. The quinazoline core has emerged as a favorable scaffold for the development of novel EGFR inhibitors due to increased affinity for the active site of EGFR kinase. Currently, there are five first-generation (gefitinib, erlotinib, lapatinib, vandetanib, and icotinib) and two second-generation (afatinib and dacomitinib) quinazoline-based EGFR inhibitors approved for the treatment of various types of cancers. The aim of this review is to outline the structural modulations favorable for the inhibitory activity toward both common mutant (del19 and L858R) and resistance-conferring mutant (T790M and C797S) EGFR forms, and provide an overview of the newly synthesized quinazoline derivatives as potentially competitive, covalent or allosteric inhibitors of EGFR. Full article
(This article belongs to the Special Issue Kinase Inhibitors in Targeted Cancer Therapy)
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