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Pharmaceuticals
Special Issues
Design and Synthesis of Small Molecule Kinase Inhibitors
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Design and Synthesis of Small Molecule Kinase Inhibitors

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

Deadline for manuscript submissions: 25 June 2024 | Viewed by 1973

Special Issue Editors

Dr. Camilla Pecoraro

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Guest Editor
Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Interests: marine alkaloids; drug discovery; cancer; anticancer drugs; small molecules kinase inhibitors; biofilm inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Daniela Carbone

E-Mail Website
Guest Editor
Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
Interests: protein kinases; biofilm; antitumor agents; antibacterial agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein kinases constitute one of the largest gene classes in eukaryotes, encompassing over 500 proteins that regulate vital cellular processes such as proliferation, cell cycle, apoptosis, metabolism, and inflammation. The hyperactivation and overexpression of kinases have been strongly linked to various cancer processes, while the ability of cancer cells to evade standard chemotherapy often stems from altered kinase activity. Consequently, the concept that inhibiting kinases could enhance cancer treatment initiated a new era of targeted therapy. Presently, the FDA has approved 82 small molecule kinase inhibitors and 9 monoclonal antibodies. Despite this substantial number, challenges persist regarding their effectiveness against diverse tumor types and the lack of selectivity. Consequently, continuous efforts are dedicated to synthesizing new molecules and investigating their potential against different protein kinases. In addition, novel techniques, such as omics analyses, help to evaluate the hyperactivated kinases in cancer, helping the design and synthesis of small molecules, encouraging the selective inhibition of pathways sustaining cancer progression and resistance. With the present special issue entitled: "Design and Synthesis of Small Molecule Kinase Inhibitors", we would like to encourage the submission of original research articles and reviews in the field, highlighting the role of novel kinases inhibitors as promising treatments in cancer.

Dr. Camilla Pecoraro
Dr. Daniela Carbone
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

  • protein kinases
  • cancer
  • small molecule kinase inhibitors
  • heterocyclic compounds
  • cancer resistance
  • targeted therapy
  • cancer-altered pathway
  • genetic mutations
  • FDA-approved kinase inhibitors
  • kinase inhibitors combinations

Published Papers (2 papers)

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Research

20 pages, 3961 KiB  
Article
Identification of Ureidocoumarin-Based Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors via Drug Repurposing Approach, Biological Evaluation, and In Silico Studies
by Ashraf K. El-Damasy, Hyun Ji Kim, Ahmed A. Al-Karmalawy, Radwan Alnajjar, Mohamed M. Khalifa, Eun-Kyoung Bang and Gyochang Keum
Pharmaceuticals 2024, 17(4), 427; https://doi.org/10.3390/ph17040427 - 27 Mar 2024
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Abstract
Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of [...] Read more.
Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment. Full article
(This article belongs to the Special Issue Design and Synthesis of Small Molecule Kinase Inhibitors)
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19 pages, 4865 KiB  
Article
Synthesis of Novel Nilotinib Analogues and Biological Evaluation of Their Antiplatelet Activity and Functionality towards Cancer Cell Proliferation In Vitro
by Louisa Pechlivani, Nikoleta Ntemou, Despoina Pantazi, Dimitrios Alivertis, Konstantinos Skobridis and Alexandros D. Tselepis
Pharmaceuticals 2024, 17(3), 349; https://doi.org/10.3390/ph17030349 - 7 Mar 2024
Viewed by 813
Abstract
Nilotinib, a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia (CML), inhibits Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells, as well as other malignancies. In the present study, new nilotinib analogues were synthesized and fully characterized. A platelet [...] Read more.
Nilotinib, a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia (CML), inhibits Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells, as well as other malignancies. In the present study, new nilotinib analogues were synthesized and fully characterized. A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated. The expression and antimetastatic effects of E-cadherin and N-cadherin were assessed. The analogues inhibited platelet aggregation in a statistically significant manner compared to nilotinib, while they exhibited a strong inhibitory effect on P-selectin and PAC-1 expression when activated by AA. All three analogues caused arrest in the mitosis phase of the HepG2 cell cycle, while analogue-1 exhibited the most potent apoptotic effect compared to nilotinib. Interestingly, none of them promoted apoptosis in HUVECs. All the analogues reduced the expression of E- and N-cadherin in different amounts, while the analogues-1 and -3 exhibited similar antimigratory effects on HepG2 cells. The results of this study reveal considerable potential to develop new tyrosine kinase inhibitors with improved antiplatelet and antitumor properties. Full article
(This article belongs to the Special Issue Design and Synthesis of Small Molecule Kinase Inhibitors)
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