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Molecules
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Protein Kinase Inhibitors: Design, Specificity and Mechanism of Action
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Protein Kinase Inhibitors: Design, Specificity and Mechanism of Action

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 4567

Special Issue Editor

Prof. Dr. William A. Denny

E-Mail Website
Guest Editor
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
Interests: small-molecule inhibitors; tyrosine kinase enzymes; PI3 kinase inhibitors; design and development; EGFR inhibitors

Special Issue Information

Dear Colleagues,

The deliberate development of small-molecule kinase inhibitors began in the early 2000s, with the approval of the BCR–ABL inhibitor imatinib in 2001. This was quickly followed by the EGFR inhibitors gefitinib and erlotinib for the treatment of non-small-cell lung cancer. The rapid evolution of tumour resistance resulted in follow-on inhibitors osimertinib, aflutinib, lazertinib and abvimertinib in current trials. A recent large expansion in the development of kinase inhibitors has been driven by two main factors: the above continuing need to develop novel analogues of inhibitors of well-studied kinases to stay ahead of the evolution of tumour resistance to kinase therapy, and a significant recent exploration of inhibitors for many more of the 500-odd members of the human kinome as their key roles in more human diseases are discovered.

The aim of this Special Issue is to provide a contemporary overview of the current state of kinase inhibitor development, whether that be inhibitors of therapy-limiting mutant variants of well-studied kinases, or novel classes of inhibitors of less well-studied members of the kinome. Inhibitors include small-molecule direct inhibitors (reversible or irreversible) of kinase function, or kinase-directed PROTACs that induce complete kinase degradation.

Prof. Dr. William A. Denny
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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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 kinase
  • inhibitor
  • drug design
  • structure–activity relationship
  • specificity
  • medicinal chemistry
  • computer modelling
  • cancer therapy

Published Papers (2 papers)

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Research

13 pages, 1814 KiB  
Article
Systematic Analysis of Covalent and Allosteric Protein Kinase Inhibitors
by Elena Xerxa, Oliver Laufkötter and Jürgen Bajorath
Molecules 2023, 28(15), 5805; https://doi.org/10.3390/molecules28155805 - 1 Aug 2023
Cited by 3 | Viewed by 1288
Abstract
In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent PKIs have long been a focal point in protein kinase (PK) drug discovery, in recent years, there has been increasing interest in [...] Read more.
In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent PKIs have long been a focal point in protein kinase (PK) drug discovery, in recent years, there has been increasing interest in allosteric PKIs (APKIs), which are expected to have high kinase selectivity. In addition, as compounds acting by covalent mechanisms experience a renaissance in drug discovery, there is also increasing interest in covalent PKIs (CPKIs). There are various reasons for this increasing interest such as the anticipated high potency, prolonged residence times compared to non-competitive PKIs, and other favorable pharmacokinetic properties. Due to the popularity of PKIs for therapeutic intervention, large numbers of PKIs and large volumes of activity data have accumulated in the public domain, providing a basis for large-scale computational analysis. We have systematically searched for CPKIs containing different reactive groups (warheads) and investigated their potency and promiscuity (multi-PK activity) on the basis of carefully curated activity data. For seven different warheads, sufficiently large numbers of CPKIs were available for detailed follow-up analysis. For only three warheads, the median potency of corresponding CPKIs was significantly higher than of non-covalent PKIs. However, for CKPIs with five of seven warheads, there was a significant increase in the median potency of at least 100-fold compared to PKI analogues without warheads. However, in the analysis of multi-PK activity, there was no general increase in the promiscuity of CPKIs compared to non-covalent PKIs. In addition, we have identified 29 new APKIs in X-ray structures of PK-PKI complexes. Among structurally characterized APKIs, 13 covalent APKIs in complexes with five PKs are currently available, enabling structure-based investigation of PK inhibition by covalent-allosteric mechanisms. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors: Design, Specificity and Mechanism of Action)
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10 pages, 1791 KiB  
Article
In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice
by Zahid Rafiq Bhat, Manvendra Kumar, Nisha Sharma, Umesh Prasad Yadav, Tashvinder Singh, Gaurav Joshi, Brahmam Pujala, Mohd Raja, Joydeep Chatterjee, Kulbhushan Tikoo, Sandeep Singh and Raj Kumar
Molecules 2022, 27(17), 5540; https://doi.org/10.3390/molecules27175540 - 28 Aug 2022
Cited by 2 | Viewed by 2767
Abstract
Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based [...] Read more.
Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors: Design, Specificity and Mechanism of Action)
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