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Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing...
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Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology

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

Deadline for manuscript submissions: 20 September 2026 | Viewed by 4026

Special Issue Editor

Dr. David Hecht

E-Mail Website
Guest Editor
1. Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA
2. Department of Chemistry, Southwestern College, Chula Vista, CA 91910, USA
Interests: ALK; machine learning; drug design; drug resistance; computational modeling; non-coding RNAs

Special Issue Information

Dear Colleagues,

This special issue will focus on the structural basis of Protein Kinase inhibitor resistance, a major challenge in cancer therapy. It will explore the intricate relationship between Protein Kinases, inhibitor binding, and the emergence of resistance mechanisms, paving the way for more effective targeted therapies and personalized treatment strategies.

This special issue will be a valuable resource for researchers, clinicians, drug developers, and other stakeholders involved in the fight against cancer. We welcome colleagues in the field to join our collection. The research contents of this special issue include but are not limited to the followings:

  1. Structural Biology of Protein Kinases: Delving into the molecular architecture of Protein Kinases, including their catalytic domains, activation mechanisms, and interactions with inhibitors.
  2. Protein Kinases Inhibitor Resistance Mechanisms: Investigating the molecular basis of resistance to Protein Kinases inhibitors, encompassing mutations, conformational changes, and alternative signaling pathways.
  3. Computational Modeling and Drug Design: Utilizing computational methods, such as molecular docking, molecular dynamics simulations, and structure-based drug design, to predict and overcome drug resistance.
  4. Preclinical and Clinical Studies: Presenting preclinical and clinical data on the efficacy and resistance profiles of TK inhibitors, including novel drug candidates.
  5. Precision Oncology Strategies: Discussing the implications of understanding Protein Kinases resistance for personalized medicine, patient selection, and treatment optimization.

Dr. David Hecht
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 250 words) can be sent to the Editorial Office for assessment.

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 inhibitor resistance
  • structural biology of of protein kinases
  • computational modeling
  • drug design
  • preclinical and clinical studies
  • precision oncology
  • ALK resistance for personalized medicine

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Published Papers (4 papers)

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Research

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38 pages, 4695 KB  
Article
Potential Mechanisms of MAP Kinase JNK’s Involvement in Modulating Cancer Cell Fate in a Cisplatin Concentration-Dependent Manner
by Monika Tenkutytė, Audronė V. Kalvelytė and Aurimas Stulpinas
Pharmaceuticals 2026, 19(3), 509; https://doi.org/10.3390/ph19030509 - 20 Mar 2026
Viewed by 564
Abstract
Background: The combination of conventional drugs and inhibitors of signaling molecules is an effective strategy to increase cancer treatment efficacy and reduce drug doses to protect against their cytotoxic effects. Our research has shown the cisplatin concentration-dependent shift in the role of MAP [...] Read more.
Background: The combination of conventional drugs and inhibitors of signaling molecules is an effective strategy to increase cancer treatment efficacy and reduce drug doses to protect against their cytotoxic effects. Our research has shown the cisplatin concentration-dependent shift in the role of MAP kinase JNK from antiapoptotic to proapoptotic in non-small cell lung cancer A549 cells. Cell death/survival signaling molecules, tumor suppressor p53 and pro-survival protein kinase AKT were detected to be differently regulated by JNK inhibition at low vs. high cisplatin concentrations. Here, we further investigated the phenomenon and potential mechanisms of combined JNK inhibition and cisplatin treatment. Methods: Cell death in vitro was evaluated by MTT and Western blot assays after combined cisplatin and specific inhibitor treatment; two-way ANOVA was used for analysis. Results: JNK is differently involved in determining cellular sensitivity to different DNA-damaging drugs. There is no universal cell death induction mechanism originating from DNA damage through the involvement of JNK. The outcome of JNK inhibition also depends on the cell type. We found that there is an unusual reciprocal interaction between p53 and AKT in cisplatin-treated A549 cells, where p53 inhibits AKT, while AKT activates p53. In the case of cisplatin + JNK inhibitor SP600125, DNA damage and reactive oxygen species (ROS) contribute to cell death regulation in different ways. ROS exert opposite roles on cell fate-determining molecules p53 and AKT, and ROS act on p53 and AKT in opposite directions at low vs. high concentrations of cisplatin, combined or not with JNK inhibition. The differentially activated p53 in response to ROS (at low versus high concentrations of cisplatin, combined with JNK inhibitor) may be a molecular switch in the role of JNK from antiapoptotic to neutral/proapoptotic, and an executor of cell death. ROS is a possible threshold regulator that, together with an as-yet-unidentified factor, can differentially regulate p53. As a result, AKT phosphorylation and function are altered. The findings emphasize the importance of assessing the role of drug concentration when combining them with JNK inhibition when monitoring therapeutic efficacy and toxicity issues in personalized cancer treatment. Full article
(This article belongs to the Special Issue Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology)
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26 pages, 3690 KB  
Article
Development of New Pyrazolo [3,4-b]Pyridine Derivatives as Potent Anti-Leukemic Agents and Topoisomerase IIα Inhibitors with Broad-Spectrum Cytotoxicity
by Wagdy M. Eldehna, Haytham O. Tawfik, Denisa Veselá, Veronika Vojáčková, Ahmed T. Negmeldin, Zainab M. Elsayed, Taghreed A. Majrashi, Petra Krňávková, Mostafa M. Elbadawi, Moataz A. Shaldam, Ghada H. Al-Ansary, Vladimír Kryštof and Hatem A. Abdel-Aziz
Pharmaceuticals 2025, 18(11), 1770; https://doi.org/10.3390/ph18111770 - 20 Nov 2025
Cited by 3 | Viewed by 1465
Abstract
Background/Objectives: In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4- [...] Read more.
Background/Objectives: In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4-b]pyridines (8a–g, 10a–g, and 12) as potential anticancer agents and Topoisomerase II inhibitors. Methods: The synthesized compounds were subjected to in vitro anticancer screening at the National Cancer Institute (NCI, USA). Active derivatives were further evaluated through a five-dose screening to determine their antiproliferative potency. Selected compounds were examined for their effects on leukemia cell lines (K562 and MV4-11), and mechanistic studies were performed to assess DNA damage, cell cycle distribution, and apoptosis-related protein modulation. Additionally, enzyme inhibition assays were conducted to determine Topoisomerase IIα (TOPIIα) inhibition. Results: Initial single-dose screening identified several active compounds, notably 8b, 8c, 8e, 8f, 10b, 10c, 10e, and 10f. Among these, compound 8c exhibited potent and broad-spectrum antiproliferative activity across the NCI cancer cell line panel, with a GI50 MG-MID value of 1.33 µM (range: 0.54–2.08 µM). The synthesized molecules showed moderate to good anti-leukemic efficacy against K562 and MV4-11 cells. Mechanistic investigations revealed that compound 8c induced DNA damage and S-phase cell cycle arrest, leading to apoptosis as evidenced by the modulation of PARP-1, Bax, XIAP, and Caspases. Furthermore, target-based assays confirmed that compound 8c significantly inhibited the DNA relaxation activity of TOPIIα in a dose-dependent manner, comparable to etoposide. Conclusions: The study highlights compound 8c as a promising pyrazolo[3,4-b]pyridine derivative with potent antiproliferative activity and effective inhibition of Topoisomerase IIα. These findings suggest its potential as a lead scaffold for further optimization in anticancer drug development.. Full article
(This article belongs to the Special Issue Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology)
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14 pages, 2282 KB  
Article
Modelling the Full-Length Inactive PKC-δ Structure to Explore Regulatory Accessibility and Selective Targeting Opportunities
by Rasha Khader and Lodewijk V. Dekker
Pharmaceuticals 2025, 18(11), 1760; https://doi.org/10.3390/ph18111760 - 18 Nov 2025
Cited by 1 | Viewed by 670
Abstract
Background/Objectives: Protein kinase C-δ (PKC-δ) is a pivotal regulator of cellular signalling, and its dysregulation contributes to oncogenesis. While certain isolated PKC-δ domains have been crystallised, the full-length architecture and interdomain interactions remain largely unresolved, limiting mechanistic insight and the design of selective [...] Read more.
Background/Objectives: Protein kinase C-δ (PKC-δ) is a pivotal regulator of cellular signalling, and its dysregulation contributes to oncogenesis. While certain isolated PKC-δ domains have been crystallised, the full-length architecture and interdomain interactions remain largely unresolved, limiting mechanistic insight and the design of selective modulators. We aimed to define the full-length, inactive conformation of PKC-δ and identify accessible, functionally relevant binding sites for ligand discovery. Methods: We generated a consensus structural model of full-length inactive PKC-δ using multi-template comparative modelling guided by established inactivity markers. Molecular docking was used to predict ligands targeting the C2 domain, which were subsequently validated in breast cancer cell models, including wild-type and C2 domain-overexpressing lines. Results: Analysis of the model revealed the architecture of the C2/V5 interdomain space, providing a structural rationale for regulation of the nuclear localisation signal (NLS). Docking identified two ligand classes: ligand 1 engaged a C2 domain surface oriented toward the C2/V5 pocket, while ligand 2 targeted the C2 domain phosphotyrosine-binding domain (PTD). Experimental validation in breast cancer cell models demonstrated that both ligands reduced cell viability; ligand 1 showed enhanced effects in C2-overexpressing cells, consistent with predicted accessibility, whereas ligand 2 partially counteracted the C2 domain-induced viability phenotype, likely via interference with PTD-mediated interactions. Conclusions: Full-length structural context is essential for identifying accessible, functionally relevant binding sites and understanding context-dependent kinase regulation. Integrating computational modelling with phenotypic validation establishes a framework for selective PKC-δ modulation, offering insights to guide ligand discovery, improve isoform selectivity, and inform strategies to mitigate kinase inhibitor resistance in precision oncology. Full article
(This article belongs to the Special Issue Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology)
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Review

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47 pages, 7059 KB  
Review
CDK4/6 Inhibitors for Breast Cancer Therapy—A Review of Clinical Trials, Structural and Computational Approaches
by Adela Avdičević, Samo Lešnik, Urban Bren and Luka Čavka
Pharmaceuticals 2026, 19(4), 610; https://doi.org/10.3390/ph19040610 - 10 Apr 2026
Viewed by 687
Abstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a central role in the regulation of cell cycle progression and represent important therapeutic targets in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. The introduction of selective CDK4/6 inhibitors, including palbociclib, ribociclib, [...] Read more.
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a central role in the regulation of cell cycle progression and represent important therapeutic targets in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. The introduction of selective CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, in combination with endocrine therapy, has significantly improved clinical outcomes and has become a standard treatment strategy in both metastatic and high-risk early-stage disease. Nevertheless, treatment resistance and disease progression remain major clinical challenges. A deeper understanding of the structural characteristics of CDK4/6 and the molecular basis of inhibitor binding is therefore essential for improving therapeutic strategies and guiding the development of new targeted agents. This review provides an integrated overview of the structural features of CDK4/6 and their role in cell cycle regulation, summarizes the clinical development and major clinical trials of currently approved CDK4/6 inhibitors, and discusses recent computational studies investigating inhibitor binding and conformational dynamics. Particular attention is given to the application of in silico approaches, including molecular docking, molecular dynamics simulations, and binding free-energy calculations, which provide insights into mechanisms of therapy resistance and potential strategies to overcome them and support the identification and optimization of novel CDK4/6-targeted therapeutic candidates. By integrating structural, clinical, and computational perspectives, this review highlights current knowledge and emerging directions in CDK4/6 research that may advance the development of more personalized therapies for HR+/HER2− breast cancer, while accounting for both intrinsic and de novo resistance mechanisms. Full article
(This article belongs to the Special Issue Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology)
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