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Molecules
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Targeting Protein Kinases for Human Diseases
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Targeting Protein Kinases for Human Diseases

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 5947

Special Issue Editors

Dr. Xin Li

E-Mail Website
Guest Editor
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA
Interests: drug design; medicinal chemistry; chemical biology; anticancer drugs; anti-infective drugs; enzyme inhibitors; protein-protein interaction (PPI) inhibitors; PROTACs
Prof. Dr. Gregory D. Cuny

E-Mail Website
Guest Editor
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
Interests: synthetic medicinal chemistry; drug design; kinase inhibitors; natural products; anti-infective drugs; inflammation

Special Issue Information

Dear Colleagues,

Protein kinases catalyze the transfer of ATP’s γ-phosphate group to serine, threonine, or tyrosine residues of target proteins. In addition, they can participate in non-enzyme functions, as well as protein–protein interactions. Collectively, protein kinases are involved in regulating an array of biological processes, including controlling almost all aspects of the cell life cycle such as division, transcription, metabolism, differentiation, and death. Dysregulation of protein kinases or mutations in their genes can directly lead to various diseases, including cancers. Recent advances in protein kinase pharmacology and structural biology have provided significantly better understanding of the biological roles of protein kinases in different diseases and accelerated the discovery of new therapeutic paradigms for modulating protein kinases for the treatment of human diseases as evidenced by the increasing number of FDA-approved drugs targeting protein kinases in addition to kinase-targeting drug candidates in clinical trials. Increasingly, protein kinases are emerging as novel targets for diseases beyond oncology, including infectious, inflammatory, immunological, and degenerative diseases. Thus, protein kinases are quickly becoming one of the favored drug classes further accelerating interest in this area and highlighting additional opportunities for the development of innovative targeted therapies for cancers and other diseases.

Dr. Xin Li
Prof. Dr. Gregory D. Cuny
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

  • drug discovery
  • kinase inhibitors
  • PROTACs
  • cancer therapy
  • drug resistance
  • cyclin-dependent kinases (CDKs)
  • tyrosine kinases
  • serine/threonine kinases

Published Papers (3 papers)

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Research

20 pages, 7017 KiB  
Article
Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
by Duangjai Todsaporn, Alexander Zubenko, Victor Kartsev, Thitinan Aiebchun, Panupong Mahalapbutr, Anthi Petrou, Athina Geronikaki, Liudmila Divaeva, Victoria Chekrisheva, Ilkay Yildiz, Kiattawee Choowongkomon and Thanyada Rungrotmongkol
Molecules 2023, 28(7), 3014; https://doi.org/10.3390/molecules28073014 - 28 Mar 2023
Cited by 3 | Viewed by 1931
Abstract
Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end, a series [...] Read more.
Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end, a series of furopyridine derivatives were evaluated for their EGFR-based inhibition and antiproliferative activities using computational and biological approaches. We found that several compounds derived from virtual screening based on a molecular docking and solvated interaction energy (SIE) method showed the potential to suppress wild-type and mutant EGFR. The most promising PD13 displayed strong inhibitory activity against wild-type (IC50 of 11.64 ± 1.30 nM), L858R/T790M (IC50 of 10.51 ± 0.71 nM), which are more significant than known drugs. In addition, PD13 revealed a potent cytotoxic effect on A549 and H1975 cell lines with IC50 values of 18.09 ± 1.57 and 33.87 ± 0.86 µM, respectively. The 500-ns MD simulations indicated that PD13 formed a hydrogen bond with Met793 at the hinge region, thus creating excellent EGFR inhibitory activity. Moreover, the binding of PD13 in the hinge region of EGFR was the major determining factor in stabilizing the interactions via hydrogen bonds and van der Waals (vdW). Altogether, PD13 is a promising novel EGFR inhibitor that could be further clinically developed as fourth-generation EGFR-TKIs. Full article
(This article belongs to the Special Issue Targeting Protein Kinases for Human Diseases)
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13 pages, 1578 KiB  
Article
Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells
by Xuan Yang, Jeffery L. Smith, Michael T. Beck, Jennifer M. Wilkinson, Ani Michaud, James D. Vasta, Matthew B. Robers and Timothy M. Willson
Molecules 2023, 28(7), 2950; https://doi.org/10.3390/molecules28072950 - 25 Mar 2023
Cited by 3 | Viewed by 1817
Abstract
PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential antitarget of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays [...] Read more.
PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential antitarget of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1, we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe 11 was used to configure NanoBRET target engagement assays for PLK1, PLK2, and PLK3 and measure the potency of several known PLK inhibitors. In-cell target engagement for PLK1 was in good agreement with the reported cellular potency for the inhibition of cell proliferation. Probe 11 enabled the investigation of the promiscuity of adavosertib, which had been described as a dual PLK1/WEE1 inhibitor in biochemical assays. Live cell target engagement analysis of adavosertib via NanoBRET demonstrated PLK activity at micromolar concentrations but only selective engagement of WEE1 at clinically relevant doses. Full article
(This article belongs to the Special Issue Targeting Protein Kinases for Human Diseases)
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17 pages, 4515 KiB  
Article
Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer
by Eslam R. El-Sawy, Zeinab A. El-Shahid, Ahmed A. F. Soliman, Amr Nassrallah, Ahmed B. Abdelwahab, Gilbert Kirsch and Heba Abdelmegeed
Molecules 2023, 28(1), 109; https://doi.org/10.3390/molecules28010109 - 23 Dec 2022
Cited by 3 | Viewed by 1485
Abstract
Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and [...] Read more.
Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer. Full article
(This article belongs to the Special Issue Targeting Protein Kinases for Human Diseases)
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