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Protein Kinase Inhibitors: Synthesis and Applications

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

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 5339

Special Issue Editors

School of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
Interests: inhibitor; neoplasms; immune system; degenerative diseases

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Guest Editor
Structural Genomics Consortium, Johann Wolfgang Goethe University, Buchmann Institute for Molecular Life Sciences, D-60438 Frankfurt am Main, Germany
Interests: residence time; chemogenomics; NanoBRET; chemical probes; kinome selectivity

Special Issue Information

Dear Colleagues,

The abnormality of protein kinase activity is involved in the pathogenesis of all kinds of diseases including cancer, inflammatory, cardiovascular, nervous and degenerative diseases, and have become one of the most important drug targets in the 21st century. Especially receptor tyrosine kinase signaling pathways have been essential targets in cancer therapy. Up to now, 89 protein kinase inhibitors have been approved and several hundreds have been used in the clinics. However, protein kinases remain to be discovered as targets for new biological processes and disease areas leading to the development and application of novel protein kinase inhibitors. Recently, ideas for the improvement of the kinome-wide selectivity of protein kinase inhibitors included covalent synthetic strategies and prolongation of the binding kinetics of the inhibitor-protein kinase complex. Selective so-called chemogenomic protein kinase inhibitors can be used as tool compounds to identify their targets in phenotypic assay systems.

This Special Issue provides a broad survey to release your most recent work on synthesis and applications, new strategies and technologies on the generation or evaluation of protein kinase inhibitors in different disease areas. Original research articles or reviews aiming at the development and applications of protein kinase inhibitors in different fields are welcome.

Dr. Cheng Wang
Dr. Benedict-Tilman Berger
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. 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

  • inhibitor
  • neoplasms
  • immune system
  • degenerative diseases
  • covalent inhibition
  • inhibitor binding kinetics
  • chemogenomic kinase inhibitors

Published Papers (2 papers)

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Research

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16 pages, 2178 KiB  
Article
Riok1, A Novel Potential Target in MSI-High p53 Mutant Colorectal Cancer Cells
by Sharon Shechter, Sapir Ya’ar Bar, Hamdan Khattib, Matthew J. Gage and Dorit Avni
Molecules 2023, 28(11), 4452; https://doi.org/10.3390/molecules28114452 - 31 May 2023
Cited by 2 | Viewed by 2433
Abstract
The vulnerabilities of cancer cells constitute a promising strategy for drug therapeutics. This paper integrates proteomics, bioinformatics, and cell genotype together with in vitro cell proliferation assays to identify key biological processes and potential novel kinases that could account, at least in part, [...] Read more.
The vulnerabilities of cancer cells constitute a promising strategy for drug therapeutics. This paper integrates proteomics, bioinformatics, and cell genotype together with in vitro cell proliferation assays to identify key biological processes and potential novel kinases that could account, at least in part, for the clinical differences observed in colorectal cancer (CRC) patients. This study started by focusing on CRC cell lines stratified by their microsatellite (MS) state and p53 genotype. It shows that cell-cycle checkpoint, metabolism of proteins and RNA, signal transduction, and WNT signaling processes are significantly more active in MSI-High p53-WT cell lines. Conversely, MSI-High cell lines with a mutant (Mut) p53 gene showed hyperactivation of cell signaling, DNA repair, and immune-system processes. Several kinases were linked to these phenotypes, from which RIOK1 was selected for additional exploration. We also included the KRAS genotype in our analysis. Our results showed that RIOK1’s inhibition in CRC MSI-High cell lines was dependent on both the p53 and KRAS genotypes. Explicitly, Nintedanib showed relatively low cytotoxicity in MSI-High with both mutant p53 and KRAS (HCT-15) but no inhibition in p53 and KRAS WT (SW48) MSI-High cells. This trend was flipped in CRC MSI-High bearing opposite p53-KRAS genotypes (e.g., p53-Mut KRAS-WT or p53-WT KRAS-Mut), where observed cytotoxicity was more extensive compared to the p53-KRAS WT-WT or Mut-Mut cells, with HCT 116 (KRAS-Mut and p53-WT) being the most sensitive to RIOK1 inhibition. These results highlight the potential of our in silico computational approach to identify novel kinases in CRC sub-MSI-High populations as well as the importance of clinical genomics in determining drug potency. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors: Synthesis and Applications)
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Review

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23 pages, 5718 KiB  
Review
Recent Progress in CDK4/6 Inhibitors and PROTACs
by Hao Wang, Jianfei Ba, Yue Kang, Zeqiao Gong, Tingting Liang, Yahong Zhang, Jianguo Qi and Jianhong Wang
Molecules 2023, 28(24), 8060; https://doi.org/10.3390/molecules28248060 - 13 Dec 2023
Cited by 4 | Viewed by 2377
Abstract
Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have [...] Read more.
Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly in treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This review provides an in-depth analysis of the action mechanism and recent advancements in CDK4/6 inhibitors, categorizing them based on their structural characteristics and origins. Furthermore, it explores proteolysis targeting chimers (PROTACs) targeting CDK4/6. We hope that this review could be of benefit for further research on CDK4/6 inhibitors and PROTACs. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors: Synthesis and Applications)
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