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Targeted Anticancer Drug Discovery
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Targeted Anticancer Drug Discovery

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

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 19088

Special Issue Editors

Dr. Halil İbrahim Ciftci

E-Mail Website
Guest Editor
1. Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur 15030, Türkiye
2. Department of Bioengineering Sciences, Izmir Katip Celebi University, Izmir 35620, Türkiye
3. Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0976, Japan
4. Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan
Interests: structure-based drug discovery; molecular simulations; drug repositioning; structural biology; molecular modelling; QSAR; virtual screening
Special Issues, Collections and Topics in MDPI journals
Dr. Belgin Sever

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey
Interests: medicinal chemistry; computational chemistry; QSAR; molecular modelling; molecular simulations; virtual screening; in silico ADME analysis; drug design and development
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Mehlika Dilek Altıntop

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Turkey
Interests: anticancer drug discovery; cancer-related kinases; drugs acting on cell death networks; small molecules; rational drug design; medicinal chemistry; heterocyclic chemistry; computational chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a multifactorial disorder rather than a single disease, and is caused by several aberrations in gene expression in the nucleus or mitochondria of cells. These alterations also trigger a homeostatic imbalance between cell division and cell death. Due to the increasing global burden of cancer and the complexity of mechanisms implicated in cancer, substantial efforts are being devoted to the management of cancer. Hitherto, many chemotherapeutics have been developed as anticancer agents, but most of them have failed in cancer treatment.

The identification of new emerging targets and the success of targeted anticancer agents have changed the paradigm of cancer therapy from traditional chemotherapy to targeted and better-tolerated therapy which aims to modulate the downstream of signaling pathways underlying tumor growth and progression. Traditional chemotherapeutic agents affect normally dividing cells as well as rapidly dividing tumor cells, and therefore their use results in severe toxicity. However, targeted therapies (e.g., small molecules, monoclonal antibodies) exert their action on specific molecular targets in tumor cells and have less effect on normal cells, leading to better cure rates as well as favorable safety profiles. Consequently, pharmaceutical research has focused on the discovery of more targeted, selective, and less-toxic anticancer agents.

This Special Issue aims to provide insight into new trends in targeted anticancer drug discovery. We are pleased to invite you to submit original research articles and reviews relevant to the identification and characterization of natural and synthetic compounds endowed with anticancer activity exerting their action on signaling pathways, proteins, and/or enzymes involved in the pathogenesis of cancer.

Research areas may include (but are not limited to) the following: inhibitors of kinases related to cancer, antitumor drugs targeting tubulin and microtubules, drugs acting on apoptotic signaling pathways, modulators of heat shock proteins (HSPs), poly-ADP ribose polymerase (PARP) inhibitors, anti-angiogenic agents, and nuclear factor-erythroid 2-related factor 2 (Nrf2) modulators.

Dr. Halil İbrahim Ciftci
Dr. Belgin Sever
Prof. Dr. Mehlika Dilek Altıntop
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

  • cancer
  • cancer therapy
  • targeted anticancer agents
  • anticancer drug discovery
  • lead identification
  • small molecules
  • signaling pathways associated with cancer
  • in silico approaches to anticancer drug design
  • specific enzyme inhibitors relevant to cancer treatment

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Published Papers (6 papers)

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Research

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38 pages, 13681 KiB  
Article
Human Estrogen Receptor Alpha Antagonists, Part 3: 3-D Pharmacophore and 3-D QSAR Guided Brefeldin A Hit-to-Lead Optimization toward New Breast Cancer Suppressants
by Nezrina Kurtanović, Nevena Tomašević, Sanja Matić, Elenora Proia, Manuela Sabatino, Lorenzo Antonini, Milan Mladenović and Rino Ragno
Molecules 2022, 27(9), 2823; https://doi.org/10.3390/molecules27092823 - 28 Apr 2022
Cited by 4 | Viewed by 3494
Abstract
The estrogen receptor α (ERα) is an important biological target mediating 17β-estradiol driven breast cancer (BC) development. Aiming to develop innovative drugs against BC, either wild-type or mutated ligand-ERα complexes were used as source data to build structure-based 3-D pharmacophore and 3-D QSAR [...] Read more.
The estrogen receptor α (ERα) is an important biological target mediating 17β-estradiol driven breast cancer (BC) development. Aiming to develop innovative drugs against BC, either wild-type or mutated ligand-ERα complexes were used as source data to build structure-based 3-D pharmacophore and 3-D QSAR models, afterward used as tools for the virtual screening of National Cancer Institute datasets and hit-to-lead optimization. The procedure identified Brefeldin A (BFA) as hit, then structurally optimized toward twelve new derivatives whose anticancer activity was confirmed both in vitro and in vivo. Compounds as SERMs showed picomolar to low nanomolar potencies against ERα and were then investigated as antiproliferative agents against BC cell lines, as stimulators of p53 expression, as well as BC cell cycle arrest agents. Most active leads were finally profiled upon administration to female Wistar rats with pre-induced BC, after which 3DPQ-12, 3DPQ-3, 3DPQ-9, 3DPQ-4, 3DPQ-2, and 3DPQ-1 represent potential candidates for BC therapy. Full article
(This article belongs to the Special Issue Targeted Anticancer Drug Discovery)
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22 pages, 5833 KiB  
Article
Distinct Mechanisms of Cytotoxicity in Novel Nitrogenous Heterocycles: Future Directions for a New Anti-Cancer Agent
by Rasha Saad Suliman, Sahar Saleh Alghamdi, Rizwan Ali, Ishrat Rahman, Tariq Alqahtani, Ibrahim K. Frah, Dimah A. Aljatli, Sarah Huwaizi, Shatha Algheribe, Zeyad Alehaideb and Imadul Islam
Molecules 2022, 27(8), 2409; https://doi.org/10.3390/molecules27082409 - 8 Apr 2022
Cited by 6 | Viewed by 2790
Abstract
Electron-rich, nitrogenous heteroaromatic compounds interact more with biological/cellular components than their non-nitrogenous counterparts. The strong intermolecular interactions with proteins, enzymes, and receptors confer significant biological and therapeutic properties to the imidazole derivatives, giving rise to a well-known and extensively used range of therapeutic [...] Read more.
Electron-rich, nitrogenous heteroaromatic compounds interact more with biological/cellular components than their non-nitrogenous counterparts. The strong intermolecular interactions with proteins, enzymes, and receptors confer significant biological and therapeutic properties to the imidazole derivatives, giving rise to a well-known and extensively used range of therapeutic drugs used for infections, inflammation, and cancer, to name a few. The current study investigates the anti-cancer properties of fourteen previously synthesized nitrogenous heterocycles, derivatives of imidazole and oxazolone, on a panel of cancer cell lines and, in addition, predicts the molecular interactions, pharmacokinetic and safety profiles of these compounds. Method: The MTT and CellTiter-Glo® assays were used to screen the imidazole and oxazolone derivatives on six cancer cell lines: HL60, MDA-MB-321, KAIMRC1, KMIRC2, MCF-10A, and HCT8. Subsequently, in vitro tubulin staining and imaging were performed, and the level of apoptosis was measured using the Promega ApoTox-Glo® triplex assay. Furthermore, several computational tools were utilized to investigate the pharmacokinetics and safety profile, including PASS Online, SEA Search, the QikProp tool, SwissADME, ProTox-II, and an in silico molecular docking study on tubulin to identify the critical molecular interactions. Results: In vitro analysis identified compounds 8 and 9 to possess the most significant potent cytotoxic activity on the HL60 and MDA-MB-231 cell lines, supported by PASS Online anti-cancer predictions with pa scores of 0.413 and 0.434, respectively. In addition, compound 9 induced caspase 3/7 dependent-apoptosis and interfered with tubulin polymerization in the MDA-MB-231 cell line, consistent with in silico docking results, identifying binding similarity to the native ligand colchicine. All the derivatives, including compounds 8 and 9, had acceptable pharmacokinetics; however, the safety profile was suboptimal for all the tested derivates except compound 4. Conclusion: The imidazole derivative compound 9 is a promising anti-cancer agent that switches on caspase-dependent apoptotic cell death and modulates microtubule function. Therefore, it could be a lead compound for further drug optimization and development. Full article
(This article belongs to the Special Issue Targeted Anticancer Drug Discovery)
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15 pages, 2078 KiB  
Article
A New Series of Indeno[1,2-c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy
by Ahmet Özdemir, Halilibrahim Ciftci, Belgin Sever, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita and Mehlika Dilek Altıntop
Molecules 2022, 27(2), 485; https://doi.org/10.3390/molecules27020485 - 13 Jan 2022
Cited by 5 | Viewed by 2105
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor [...] Read more.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC. Full article
(This article belongs to the Special Issue Targeted Anticancer Drug Discovery)
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14 pages, 2973 KiB  
Communication
Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance
by Olga E. Andreeva, Danila V. Sorokin, Ekaterina I. Mikhaevich, Irina V. Bure, Yuri Y. Shchegolev, Marina V. Nemtsova, Margarita V. Gudkova, Alexander M. Scherbakov and Mikhail A. Krasil’nikov
Molecules 2021, 26(21), 6661; https://doi.org/10.3390/molecules26216661 - 3 Nov 2021
Cited by 15 | Viewed by 2720
Abstract
Hormone therapy is one of the most effective breast cancer treatments, however, its application is limited by the progression of hormonal resistance, both primary or acquired. The development of hormonal resistance is caused either by an irreversible block of hormonal signalling (suppression of [...] Read more.
Hormone therapy is one of the most effective breast cancer treatments, however, its application is limited by the progression of hormonal resistance, both primary or acquired. The development of hormonal resistance is caused either by an irreversible block of hormonal signalling (suppression of the activity or synthesis of hormone receptors), or by activation of oestrogen-independent signalling pathways. Recently the effect of exosome-mediated intercellular transfer of hormonal resistance was revealed, however, the molecular mechanism of this effect is still unknown. Here, the role of exosomal miRNAs (microRNAs) in the transferring of hormonal resistance in breast cancer cells has been studied. The methods used in the work include extraction, purification and RNAseq of miRNAs, transfection of miRNA mimetics, immunoblotting, reporter analysis and the MTT test. Using MCF7 breast cancer cells and MCF7/T tamoxifen-resistant sub-line, we have found that some miRNAs, suppressors of oestrogen receptor signalling, are overexpressed in the exosomes of the resistant breast cancer cells. The multiple (but not single) transfection of one of the identified miRNA, miR-181a-2, into oestrogen-dependent MCF7 cells induced the irreversible tamoxifen resistance associated with the continuous block of the oestrogen receptor signalling and the activation of PI3K/Akt pathway. We suppose that the miRNAs-ERα suppressors may act as trigger agents inducing the block of oestrogen receptor signalling and breast cancer cell transition to an aggressive oestrogen-independent state. Full article
(This article belongs to the Special Issue Targeted Anticancer Drug Discovery)
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Review

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24 pages, 5184 KiB  
Review
A Comprehensive Overview of the Developments of Cdc25 Phosphatase Inhibitors
by Ahmed Bakr Abdelwahab, Eslam Reda El-Sawy, Atef G. Hanna, Denyse Bagrel and Gilbert Kirsch
Molecules 2022, 27(8), 2389; https://doi.org/10.3390/molecules27082389 - 7 Apr 2022
Cited by 5 | Viewed by 2984
Abstract
Cdc25 phosphatases have been considered promising targets for anticancer development due to the correlation of their overexpression with a wide variety of cancers. In the last two decades, the interest in this subject has considerably increased and many publications have been launched concerning [...] Read more.
Cdc25 phosphatases have been considered promising targets for anticancer development due to the correlation of their overexpression with a wide variety of cancers. In the last two decades, the interest in this subject has considerably increased and many publications have been launched concerning this issue. An overview is constructed based on data analysis of the results of the previous publications covering the years from 1992 to 2021. Thus, the main objective of the current review is to report the chemical structures of Cdc25s inhibitors and answer the question, how to design an inhibitor with better efficacy and lower toxicity? Full article
(This article belongs to the Special Issue Targeted Anticancer Drug Discovery)
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31 pages, 3938 KiB  
Review
Recent Advancements in the Development of Anti-Breast Cancer Synthetic Small Molecules
by Eslam B. Elkaeed, Hayam A. Abd El Salam, Ahmed Sabt, Ghada H. Al-Ansary and Wagdy M. Eldehna
Molecules 2021, 26(24), 7611; https://doi.org/10.3390/molecules26247611 - 15 Dec 2021
Cited by 10 | Viewed by 3586
Abstract
Among all cancer types, breast cancer (BC) still stands as one of the most serious diseases responsible for a large number of cancer-associated deaths among women worldwide, and diagnosed cases are increasing year by year worldwide. For a very long time, hormonal therapy, [...] Read more.
Among all cancer types, breast cancer (BC) still stands as one of the most serious diseases responsible for a large number of cancer-associated deaths among women worldwide, and diagnosed cases are increasing year by year worldwide. For a very long time, hormonal therapy, surgery, chemotherapy, and radiotherapy were used for breast cancer treatment. However, these treatment approaches are becoming progressively futile because of multidrug resistance and serious side effects. Consequently, there is a pressing demand to develop more efficient and safer agents that can fight breast cancer belligerence and inhibit cancer cell proliferation, invasion and metastasis. Currently, there is an avalanche of newly designed and synthesized molecular entities targeting multiple types of breast cancer. This review highlights several important synthesized compounds with promising anti-BC activity that are categorized according to their chemical structures. Full article
(This article belongs to the Special Issue Targeted Anticancer Drug Discovery)
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