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Pharmaceuticals
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Kinase Inhibitors in Targeted Cancer Therapy
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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: closed (19 April 2024) | Viewed by 10138

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 Issues, Collections and Topics in MDPI journals

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 (5 papers)

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Research

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31 pages, 5513 KiB  
Article
Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta
by Sara Calenda, Daniela Catarzi, Flavia Varano, Erica Vigiani, Rosaria Volpini, Catia Lambertucci, Andrea Spinaci, Letizia Trevisan, Ilenia Grieco, Stephanie Federico, Giampiero Spalluto, Gianluca Novello, Veronica Salmaso, Stefano Moro and Vittoria Colotta
Pharmaceuticals 2024, 17(4), 468; https://doi.org/10.3390/ph17040468 - 07 Apr 2024
Viewed by 613
Abstract
Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties [...] Read more.
Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson’s and Alzheimer’s diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1–32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13–32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor–kinase interactions. Full article
(This article belongs to the Special Issue Kinase Inhibitors in Targeted Cancer Therapy)
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22 pages, 3974 KiB  
Article
Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation
by Kyaw Zwar Myint, Brinda Balasubramanian, Simran Venkatraman, Suchada Phimsen, Supisara Sripramote, Jeranan Jantra, Chaiwat Choeiphuk, Somkit Mingphruedhi, Paramin Muangkaew, Narongsak Rungsakulkij, Pongsatorn Tangtawee, Wikran Suragul, Watoo Vassanasiri Farquharson, Kanokpan Wongprasert, Somchai Chutipongtanate, Pimtip Sanvarinda, Marisa Ponpuak, Naravat Poungvarin, Tavan Janvilisri, Tuangporn Suthiphongchai, Kiren Yacqub-Usman, Anna M. Grabowska, David O. Bates and Rutaiwan Tohtongadd Show full author list remove Hide full author list
Pharmaceuticals 2024, 17(2), 197; https://doi.org/10.3390/ph17020197 - 02 Feb 2024
Viewed by 943
Abstract
Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed [...] Read more.
Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib’s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations. Full article
(This article belongs to the Special Issue Kinase Inhibitors in Targeted Cancer Therapy)
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19 pages, 2841 KiB  
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
Cited by 1 | Viewed by 982
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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19 pages, 18215 KiB  
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
Cited by 1 | Viewed by 1320
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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40 pages, 15975 KiB  
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 8 | Viewed by 5406
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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