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Kinase Inhibitors and Kinase-Targeted Cancer Therapies
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Kinase Inhibitors and Kinase-Targeted Cancer Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 5506

Special Issue Editor

Dr. Olivier E. Pardo

E-Mail Website
Guest Editor
Division of Cancer, Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London W12 0NN, UK
Interests: cancer drug resistance and metastasis; S6 kinases; drug development and repurposing

Special Issue Information

Dear Colleagues,

The advent of targeted therapies has revolutionized the clinical management of cancer by providing alternatives to the use of systematically toxic chemotherapy and locally damaging radiotherapy. Kinase inhibitors comprise an important part of this new arsenal and are now used in first-line therapy in bespoke cancer settings. Historically, these inhibitors have been reversible ATP competitors, often suffering from a lack of selectivity and being rapidly counteracted by the development of drug resistance. However, novel classes of inhibitors have now emerged, showing drastically improved selectivity (including to particular mutational states of their targets) and pharmacodynamic properties, including irreversible binding. Additionally, alternative mechanisms of action that avoid targeting the ATP binding sites, such as allosteric modulation or degradation, have further improved selectivity amongst phylogenetically related targets and enabled the circumvention of traditional resistance pathways.

This Special Issue of IJMS is calling for both original articles and reviews that present novel findings and summative assessments of advances in kinase inhibition.

Dr. Olivier E. Pardo
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • kinase activity inhibitors
  • degraders
  • antibodies
  • nanobodies
  • protein–kinase interaction inhibitors

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Published Papers (3 papers)

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Research

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18 pages, 2898 KiB  
Article
Investigating the Regulation of Ribosomal Protein S6 Kinase 1 by CoAlation
by Oksana Malanchuk, Anna Bdzhola, Sergii Palchevskyi, Volodymyr Bdzhola, Peng Chai, Olivier E. Pardo, Michael J. Seckl, Adrija Banerjee, Sew Yeu Peak-Chew, Mark Skehel, Lalitha Guruprasad, Alexander Zhyvoloup, Ivan Gout and Valeriy Filonenko
Int. J. Mol. Sci. 2024, 25(16), 8747; https://doi.org/10.3390/ijms25168747 - 11 Aug 2024
Viewed by 676
Abstract
Ribosomal protein S6 kinases belong to a family of highly conserved enzymes in eukaryotes that regulate cell growth, proliferation, survival, and the stress response. It is well established that the activation and downstream signalling of p70S6Ks involve multiple phosphorylation events by key regulators [...] Read more.
Ribosomal protein S6 kinases belong to a family of highly conserved enzymes in eukaryotes that regulate cell growth, proliferation, survival, and the stress response. It is well established that the activation and downstream signalling of p70S6Ks involve multiple phosphorylation events by key regulators of cell growth, survival, and energy metabolism. Here, we report for the first time the covalent modification of p70S6K1 by coenzyme A (CoA) in response to oxidative stress, which regulates its kinase activity. The site of CoA binding (CoAlation) was mapped by mass spectrometry to cysteine 217 (Cys217), located in the kinase activation loop and only one amino acid away from the tripeptide DFG motif, which facilitates ATP-binding. The CoAlation of recombinant p70S6K1 was demonstrated in vitro and was shown to inhibit its kinase activity. Our molecular docking and dynamics analysis revealed the most likely mode for CoA binding to p70S6K1. This mechanism involves the non-covalent binding of the CoA ADP moiety to the p70S6K1 nucleotide-binding pocket, positioning the CoA thiol group in close proximity to form a covalent bond with the surface-exposed Cys217 residue. These findings support a “dual anchor” mechanism for protein kinase inhibition by CoAlation in cellular response to oxidative stress. Furthermore, the inhibition of S6K1 by CoAlation may open new avenues for developing novel inhibitors. Full article
(This article belongs to the Special Issue Kinase Inhibitors and Kinase-Targeted Cancer Therapies)
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13 pages, 1882 KiB  
Article
Benefits of NGS in Advanced Lung Adenocarcinoma Vary by Populations and Timing of Examination
by Po-Hsin Lee, Wei-Fan Ou, Yen-Hsiang Huang, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Gee-Chen Chang and Tsung-Ying Yang
Int. J. Mol. Sci. 2024, 25(13), 6949; https://doi.org/10.3390/ijms25136949 - 25 Jun 2024
Viewed by 989
Abstract
Despite the widespread application of next-generation sequencing (NGS) in advanced lung adenocarcinoma, its impact on survival and the optimal timing for the examination remain uncertain. This cohort study included advanced lung adenocarcinoma patients who underwent NGS testing. We categorized patients into four groups: [...] Read more.
Despite the widespread application of next-generation sequencing (NGS) in advanced lung adenocarcinoma, its impact on survival and the optimal timing for the examination remain uncertain. This cohort study included advanced lung adenocarcinoma patients who underwent NGS testing. We categorized patients into four groups: Group 1: treatment-naïve, upfront NGS; Group 2: Treatment-naïve, exclusionary EGFR/ALK/ROS1; Group 3: post-treatment, no known EGFR/ALK/ROS1; Group 4: known driver mutation and post-TKI treatment. A total of 424 patients were included. There were 128, 126, 90, and 80 patients in Groups 1, 2, 3, and 4, respectively. In Groups 1, 2, 3, and 4, targetable mutations were identified in 76.6%, 49.2%, 41.1%, and 33.3% of the patients, respectively (p < 0.001). Mutation-targeted treatments were applied in 68.0%, 15.1%, 27.8%, and 22.5% of the patients, respectively (p < 0.001). In the overall population, patients receiving mutation-targeted treatments exhibited significantly longer overall survival (OS) (aHR 0.54 [95% CI 0.37–0.79], p = 0.001). The most profound benefit was seen in the Group 1 patients (not reached vs. 40.4 months, p = 0.028). The median OS of patients with mutation-targeted treatments was also significantly longer among Group 2 patients. The median post-NGS survival of patients receiving mutation-targeted treatments was numerically longer in Group 3 and Group 4 patients. In conclusion, mutation-targeted therapy is associated with a favorable outcome. However, the opportunities of NGS-directed treatment and the survival benefits of mutation-targeted treatment were various among different populations. Full article
(This article belongs to the Special Issue Kinase Inhibitors and Kinase-Targeted Cancer Therapies)
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Review

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33 pages, 4381 KiB  
Review
Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives
by Jiahao Li, Chen Gong, Haiting Zhou, Junxia Liu, Xiaohui Xia, Wentao Ha, Yizhi Jiang, Qingxu Liu and Huihua Xiong
Int. J. Mol. Sci. 2024, 25(10), 5489; https://doi.org/10.3390/ijms25105489 - 17 May 2024
Cited by 4 | Viewed by 3414
Abstract
Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such [...] Read more.
Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition. Full article
(This article belongs to the Special Issue Kinase Inhibitors and Kinase-Targeted Cancer Therapies)
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