Ahmed A. Al-Karmalawy1,2*
Hussein I. El-Subbagh3,4
Liliya Logoyda5
Roman B. Lesyk6
Mohammed I. El-Gamal3,7,8- 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt
- 2Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
- 3Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- 4Pharmacy Center of Scientific Excellence, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- 5Department of Pharmaceutical Chemistry, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
- 6Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National University, Lviv, Ukraine
- 7Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- 8Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
Editorial on the Research Topic
Recent advances in the research and development of kinase-inhibitory anticancer molecules
Protein kinases (PKs) represent one of the most important targets in the discovery of new drug candidates in oncology based on their crucial roles in the processes of cellular growth and proliferation (Fabbro et al., 2002). Kinase inhibitors are classified into 1) type I kinase inhibitors (interacting directly with the ATP binding site), 2) type II kinase inhibitors (interacting with the ATP binding site besides extra hydrophobic interactions to adjacent hydrophobic pocket), 3) type III kinase inhibitors or allosteric inhibitors (interacting with a hydrophobic pocket distant from the ATP binding site), and 4) others (such as covalent and protein substrate competitive inhibitors) (Chahrour et al., 2012).
However, most of the currently available kinase inhibitors were recorded to be less effective over time, especially in the treatment of complex and mutagenic tumors due to their design to act on a single target. On the contrary, multitargeted kinase inhibitors were observed to be more effective due to their ability to inhibit multiple pathways in cancer cell proliferation which results in decreasing the possibility of drug resistance development (Guo and Ma, 2021; El-Naggar et al., 2022).
Herein, four research articles were published on this Research Topic received from China, Sudan, Saudi Arabia, and Germany. https://www.frontiersin.org/research-topics/33242/recent-advances-in-the-research-and-development-of-kinase-inhibitory-anticancer-molecules.
Not only synthetic medicinal chemistry contributes to the discovery and development of kinase inhibitors, many natural compounds also have been reported as kinase inhibitors. In the original research article of Tian et al., inhibitors isolated from Zanthoxylum simulans were reported as inhibitors of multiple janus kinases (JAKs). The authors developed JAKs based affinity ultrafiltration method coupled with LC/Q-TOF-MS to enable them to study the affinity of Z. simulans quaternary alkaloids against JAKs. They discovered that Berberine and Chelerythrine exhibited superior selectivity against JAK1, JAK2, and JAK3 over Tyk2. Chelerythrine demonstrated promising antiproliferative activity against AGS gastric cancer cells. Both Berberine and Chelerythrine showed obvious inhibition against LO2 human hepatocyte cells. Chelerythrine-mediated inhibition and apoptosis against AGS cells happened via the Estrogen Pathway. This is in addition to direct inhibition of JAK1, JAK2, and JAK3 kinases. The authors studied the putative binding interactions of the quaternary alkaloids to reveal the reasons for the selectivity towards the three JAK isozymes.
The other article authored by Mohamed et al. reported another contribution of natural products to kinase inhibitors discovery. In silico studies including molecular docking, molecular dynamic simulation, and pharmacophore modeling led to discovery of dual MNK/PIM as potential antiproliferative candidates for treatment of acute myeloid leukemia. The authors started their study with pharmacophore modeling of ligands bound to MNK-2 and PIM-2 crystal structures, and the obtained pharmacophoric features were screened against 270,540 natural compounds from ZINC database. The matched natural compounds were docked into the binding sites of MNK-2 and PIM-2 kinases.
The original research article by Fu et al. reported the design and synthesis of a series of flavone-based cyclin-dependent kinase 1 (CDK1) inhibitors. The most potent CDK1 inhibitor among this series exhibited higher inhibitory activity against RAW 264.7 than MCF-7 cells. This hit compound can be useful for further optimization towards antiproliferative and anti-inflammatory candidates development. The authors studied the putative binding interactions of the most active inhibitor with CDK1 crystal structure.
The fourth published article entitled Heine et al. (Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non-small cell lung cancer), where the authors investigated the effect of alectinib and crizotinib on human monocyte-derived DCs (moDC) as the most powerful antigen-presenting cells. Crizotinib-treated DCs were observed to reduce the activation markers such as CD83, chemokine-guided migration, antigen uptake, and pro-inflammatory cytokines, especially Interleukin-12. These effects were superior to those of alectinib and therefore crizotinib could dampen the anti-tumor immunity more effectively. Briefly, crizotinib alone was confirmed to have immunosuppressive effects on DCs phenotype and reduced DC function, accordingly potentially impairing anti-tumor immunity.
Author contributions
AA-K: Conceptualization, Investigation, Project administration, Resources, Supervision, Writing–original draft, Writing–review and editing. HE-S: Project administration, Resources, Supervision, Writing–review and editing. LL: Writing–review and editing. RL: Writing–review and editing. ME-G: Data curation, Project administration, Writing–original draft, Writing–review and editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Chahrour, O., Cairns, D., and Omran, Z. (2012). Small molecule kinase inhibitors as anti-cancer therapeutics. Mini Rev. Med. Chem. 12, 399–411. doi:10.2174/138955712800493915
El-Naggar, A. M., Hassan, A. M. A., Elkaeed, E. B., Alesawy, M. S., and Al-Karmalawy, A. A. (2022). Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2. Bioorg. Chem. 123, 105770. doi:10.1016/j.bioorg.2022.105770
Fabbro, D., Ruetz, S., Buchdunger, E., Cowan-Jacob, S. W., Fendrich, G., Liebetanz, J., et al. (2002). Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol. Ther. 93, 79–98. doi:10.1016/s0163-7258(02)00179-1
Keywords: protein kinases, kinase inhibitors, rational design, multitargeted kinase inhibitors, anticancer
Citation: Al-Karmalawy AA, El-Subbagh HI, Logoyda L, Lesyk RB and El-Gamal MI (2023) Editorial: Recent advances in the research and development of kinase-inhibitory anticancer molecules. Front. Chem. 11:1328424. doi: 10.3389/fchem.2023.1328424
Received: 26 October 2023; Accepted: 03 November 2023;
Published: 09 November 2023.
Edited and reviewed by:
Michael Kassiou, The University of Sydney, AustraliaCopyright © 2023 Al-Karmalawy, El-Subbagh, Logoyda, Lesyk and El-Gamal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ahmed A. Al-Karmalawy, akarmalawy@horus.edu.eg