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Special Issue "Activity, Function and Druggability of Cancer-Related Enzymes"

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

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Dr. Alessio Nocentini
E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019 Florence, Italy
Interests: medicinal chemistry; drug design; computational chemistry; carbonic anhydrases; enzymatic evaluation
Dr. Wagdy M. Eldehna
E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Egypt
Interests: drug design; medicinal chemistry; pharmaceutical organic synthesis
Dr. Stanislav Kalinin
E-Mail Website
Guest Editor
Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia
Interests: medicinal chemistry; drug design; enzyme inhibition; multicomponent reactions

Special Issue Information

Dear colleagues,

Cancer remains a major cause of mortality and morbidity worldwide despite numerous studies have been and are being conducted to improve tumor prevention, early diagnosis and treatment.

Traditionally, several enzymes regulating cell division or involved in DNA replication have been considered valuable anticancer drug targets. Furthermore, alterations of the energy metabolism are among the main hallmarks of cancers making targeting glycolytic pathway enzymes an effective means for treating the disease. Finally, several enzymes have been used as biomarkers for cancer identification and validation being under- or over-expressed in various tumors. As a result, many such enzymes have been also validated as targets for therapeutic intervention. Accordingly, ​several main classes of cancer-related enzymes can be allocated, such as:

  1. Glycolytic enzymes (e.g. lactate dehydrogenase A, glucose-6-phosphate dehydrogenase)
  2. Oncogenic signal transduction enzymes (e.g. kinases, phosphatases)
  3. DNA-related enzymes (e.g. DNA polymerase, topoisomerase, telomerase)
  4. Extracellular enzymes (e.g. carbonic anhydrases, matrix metalloproteases, ecto-5′-nucleotidase)

It is noteworthy that nonglycolytic enzymes such as carbonic anhydrases (CAs) IX and XII play a major role in the metabolic switch of tumor cells. Indeed, the resulting intracellular acidosis, incompatible with basic cellular functions, induces tumor cells to activate complex molecular mechanisms, actively involving CA IX and XII among other proteins, that restore the intracellular pH and acidify the extracellular pH to promote cancer survival and proliferation.

Targeting enzymatic variations of tumor cells shown to be associated with cancer progression offers a huge potential and remains a largely unexplored topic for developing new anti-cancer therapies. This Special Issue is dedicated to all important advances in the field of cancer-related enzymes as biomarkers and therapeutic targets for the diagnosis and treatment of tumors.

Original papers, reviews articles, and perspectives from experts in the field are welcome.

Dr. Alessio Nocentini
Dr. Wagdy M. Eldehna
Dr. Stanislav Kalinin
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 papers will be 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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Enzyme
  • Cancer
  • Glycolysis
  • Metabolic switch
  • Cancer epigenetics
  • Signal transduction
  • Biomarker
  • Therapy

Published Papers (8 papers)

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Research

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Article
Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors
Int. J. Mol. Sci. 2021, 22(23), 12738; https://doi.org/10.3390/ijms222312738 - 25 Nov 2021
Viewed by 177
Abstract
A novel class of potential protein kinase inhibitors 716 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC50 values for compounds 7 and [...] Read more.
A novel class of potential protein kinase inhibitors 716 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC50 values for compounds 7 and 10 were 2.27 and 2.53 μM for K562 cells, 1.42 and 1.52 μM for HL-60 cells, and 4.56 and 24.77 μM for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase, preventing the cell division of OKP-GS cells. Compounds 7, 9, and 10 showed 36–45% inhibitory activity against PDGFRα and PDGFRβ at the concentration of 1 μM. Molecular modeling experiments showed that obtained compounds could bind to PDGFRα as either type 1 (compound 7, ATP-competitive) or type 2 (compound 10, allosteric) inhibitors, depending on the substituent in the amide part of the molecule. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Article
Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors
Int. J. Mol. Sci. 2021, 22(20), 11119; https://doi.org/10.3390/ijms222011119 - 15 Oct 2021
Viewed by 232
Abstract
A new series of quinoline-based benzenesulfonamides (QBS) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc [...] Read more.
A new series of quinoline-based benzenesulfonamides (QBS) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group (QBS 13ac); thereafter, the sulphonamide group was switched to ortho- and meta-positions to afford regioisomers 9ad and 11ag. Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS 16. All the described QBS have been synthesized and investigated for their CA inhibitory action against hCA I, II, IX and XII. In general, para-sulphonamide derivatives 13ac displayed the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 11c (KI = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Article
Blockade of Glycosphingolipid Synthesis Inhibits Cell Cycle and Spheroid Growth of Colon Cancer Cells In Vitro and Experimental Colon Cancer Incidence In Vivo
Int. J. Mol. Sci. 2021, 22(19), 10539; https://doi.org/10.3390/ijms221910539 - 29 Sep 2021
Viewed by 351
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in humans. At early stages CRC is treated by surgery and at advanced stages combined with chemotherapy. We examined here the potential effect of glucosylceramide synthase (GCS)-inhibition on CRC biology. GCS is [...] Read more.
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in humans. At early stages CRC is treated by surgery and at advanced stages combined with chemotherapy. We examined here the potential effect of glucosylceramide synthase (GCS)-inhibition on CRC biology. GCS is the rate-limiting enzyme in the glycosphingolipid (GSL)-biosynthesis pathway and overexpressed in many human tumors. We suppressed GSL-biosynthesis using the GCS inhibitor Genz-123346 (Genz), NB-DNJ (Miglustat) or by genetic targeting of the GCS-encoding gene UDP-glucose-ceramide-glucosyltransferase- (UGCG). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. UGCG silencing strongly also inhibited tumor spheroid growth in Lovo cells and moderately in HCT116 cells. MS/MS analysis demonstrated markedly elevated levels of sphingomyelin (SM) and phosphatidylcholine (PC) that occurred in a Genz-concentration dependent manner. Ultrastructural analysis of Genz-treated cells indicated multi-lamellar lipid storage in vesicular compartments. In mice, Genz lowered the incidence of experimentally induced colorectal tumors and in particular the growth of colorectal adenomas. These results highlight the potential for GCS-based inhibition in the treatment of CRC. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Article
Design, Synthesis and Anticancer Profile of New 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect
Int. J. Mol. Sci. 2021, 22(19), 10491; https://doi.org/10.3390/ijms221910491 - 28 Sep 2021
Viewed by 534
Abstract
A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a–n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed [...] Read more.
A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a–n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Article
Synergistic Interactions of Cannabidiol with Chemotherapeutic Drugs in MCF7 Cells: Mode of Interaction and Proteomics Analysis of Mechanisms
Int. J. Mol. Sci. 2021, 22(18), 10103; https://doi.org/10.3390/ijms221810103 - 18 Sep 2021
Viewed by 1246
Abstract
Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN−38) [...] Read more.
Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN−38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN−38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II β and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN−38 (CSN−38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN−38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of CBD and its synergistic combination with SN−38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Review

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Review
Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential
Int. J. Mol. Sci. 2021, 22(19), 10253; https://doi.org/10.3390/ijms221910253 - 23 Sep 2021
Cited by 1 | Viewed by 445
Abstract
CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the [...] Read more.
CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Review
The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer
Int. J. Mol. Sci. 2021, 22(12), 6535; https://doi.org/10.3390/ijms22126535 - 18 Jun 2021
Viewed by 1289
Abstract
Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human [...] Read more.
Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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Review
Functional Roles of SPINK1 in Cancers
Int. J. Mol. Sci. 2021, 22(8), 3814; https://doi.org/10.3390/ijms22083814 - 07 Apr 2021
Viewed by 663
Abstract
Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) is a secreted protein known as a protease inhibitor of trypsin in the pancreas. However, emerging evidence shows its function in promoting cancer progression in various types of cancer. SPINK1 modulated tumor malignancies and induced the [...] Read more.
Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) is a secreted protein known as a protease inhibitor of trypsin in the pancreas. However, emerging evidence shows its function in promoting cancer progression in various types of cancer. SPINK1 modulated tumor malignancies and induced the activation of the downstream signaling of epidermal growth factor receptor (EGFR) in cancer cells, due to the structural similarity with epidermal growth factor (EGF). The discoverable SPINK1 somatic mutations, expressional signatures, and prognostic significances in various types of cancer have attracted attention as a cancer biomarker in clinical applications. Emerging findings further clarify the direct and indirect biological effects of SPINK1 in regulating cancer proliferation, metastasis, drug resistance, transdifferentiation, and cancer stemness, warranting the exploration of the SPINK1-mediated molecular mechanism to identify a therapeutic strategy. In this review article, we first integrate the transcriptomic data of different types of cancer with clinical information and recent findings of SPINK1-mediated malignant phenotypes. In addition, a comprehensive summary of SPINK1 expression in a pan-cancer panel and individual cell types of specific organs at the single-cell level is presented to indicate the potential sites of tumorigenesis, which has not yet been reported. This review aims to shed light on the roles of SPINK1 in cancer and provide guidance and potential directions for scientists in this field. Full article
(This article belongs to the Special Issue Activity, Function and Druggability of Cancer-Related Enzymes)
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