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Pharmaceuticals
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Small Molecules in Targeted Cancer Therapy and Diagnosis
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Small Molecules in Targeted Cancer Therapy and Diagnosis

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 15 July 2025 | Viewed by 13800

Special Issue Editor

Dr. Francesca Musumeci

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
Interests: pyrazolo[3,4-d]pyrimidines; kinase inhibitors; anticancer agents; small molecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer remains a significant global health challenge, necessitating innovative approaches to improve patient outcomes. In recent years, targeted cancer therapy and diagnosis has witnessed remarkable advancements driven by small molecules. These compounds offer promising avenues for precise cancer treatment and accurate disease detection, providing personalized and effective interventions. This Special Issue aims to highlight the latest developments in small molecule-based approaches for targeted cancer therapy and diagnosis and addresses the associated challenges. In particular, it will provide insights into the design, synthesis, and characterization of small molecules, including inhibitors, activators, modulators, and imaging agents. Emphasis will be placed on their mechanisms of action, molecular interactions, and potential for targeted cancer therapy and diagnosis.

Topics of interest may include, but are not limited to, the following:

  • Rational design and synthesis of small molecules targeting specific oncogenic targets, such as kinases, receptors, and transcription factors.
  • Small molecules as modulators of immune responses in cancer immunotherapy.
  • Application of small molecules in combination therapies to overcome drug resistance.
  • Strategies for targeted drug delivery utilizing small molecule conjugates or nanocarriers.
  • Computational modeling and virtual screening techniques for the design of small molecules with enhanced selectivity and potency.
  • Pharmacokinetic and pharmacodynamic considerations in small molecule-based cancer therapy and diagnosis.
  • Small molecule-based imaging agents for cancer diagnosis, including optical, radioactive, and magnetic resonance imaging (MRI) probes.
  • Development of theranostic agents in cancers.

This Special Issue aims to bring together researchers from diverse disciplines to present their cutting-edge research, share insights, and foster collaborations. The ultimate goal is to accelerate the translation of small molecule-based approaches into clinical applications, thereby improving the lives of cancer patients. We invite researchers to contribute their research articles or reviews to this Special Issue.

Dr. Francesca Musumeci
Guest Editor

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • small molecules
  • cancer therapy
  • cancer diagnosis
  • targeted therapy
  • theranostic agents

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Published Papers (6 papers)

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Research

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17 pages, 5171 KiB  
Article
Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures
by Mariana Nunes and Sara Ricardo
Pharmaceuticals 2025, 18(1), 14; https://doi.org/10.3390/ph18010014 - 25 Dec 2024
Viewed by 2744
Abstract
Background: Chemoresistance is a major obstacle in high-grade serous carcinoma (HGSC) treatment. Although many patients initially respond to chemotherapy, the majority of them relapse due to Carboplatin and Paclitaxel resistance. Drug repurposing has surfaced as a potentially effective strategy that works synergically with [...] Read more.
Background: Chemoresistance is a major obstacle in high-grade serous carcinoma (HGSC) treatment. Although many patients initially respond to chemotherapy, the majority of them relapse due to Carboplatin and Paclitaxel resistance. Drug repurposing has surfaced as a potentially effective strategy that works synergically with standard chemotherapy to bypass chemoresistance. In a prior study, using 2D cultures and two HGSC chemoresistant cell lines, it was demonstrated that combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin resulted in the most notable synergy. Acknowledging that 2D culture systems are limited in reflecting the tumor architecture, 3D cultures were generated to provide insights on treatment efficacy tests in more complex models. Objectives: We aimed to investigate whether combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin offers therapeutic benefits in a Cultrex-based 3D model. Methods: Here, the cytotoxicity of Carboplatin and Paclitaxel, both alone and in combination with Pitavastatin or Ivermectin, were analyzed on two chemoresistant tumor cell lines, OVCAR8 and OVCAR8 PTX R C, in 3D cultures. Cellular viability was assessed using CellTiter-Glo® Luminescent assays. Also, it explored synergistic interactions using zero interaction potency, Loewe, Bliss independence, and High-single agent reference models. Results: Our research indicates combining chemotherapeutic drugs with Pitavastatin or Ivermectin yields significantly more cytotoxic effects than chemotherapy alone. For all the combinations tested, at least one model indicated an additive effect; however, only the combination of Paclitaxel and Ivermectin consistently demonstrated an additive effect across all chemoresistant cell lines cultured in 3D models, as well as in all four synergy reference models used to assess drug interactions. Conclusions: Combining Paclitaxel with Ivermectin has the highest cytotoxic and the strongest additive effect for both chemoresistant cell lines compared to Paclitaxel alone. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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19 pages, 3190 KiB  
Article
Therapeutic, Clinicopathological, and Molecular Correlates of PRKACA Expression in Gastrointestinal Cancers
by Ayoub Al Othaim, Glowi Alasiri and Abdulaziz Alfahed
Pharmaceuticals 2024, 17(10), 1263; https://doi.org/10.3390/ph17101263 - 25 Sep 2024
Viewed by 1403
Abstract
Background/Objectives: PRKACA alterations have clear diagnostic and biological roles in the fibrolamellar variant of hepatocellular carcinoma and a potential predictive role in that cancer type. However, the roles of PRKACA have not been comprehensively examined in gastric and colorectal cancers (GC and CRC). [...] Read more.
Background/Objectives: PRKACA alterations have clear diagnostic and biological roles in the fibrolamellar variant of hepatocellular carcinoma and a potential predictive role in that cancer type. However, the roles of PRKACA have not been comprehensively examined in gastric and colorectal cancers (GC and CRC). This study, therefore, sought to investigate the roles of PRKACA expression in GC and CRC. Methods: The clinico-genomic data of 441 GC and 629 CRC cases were analyzed for therapeutic, clinicopathological, and biological correlates using appropriate bioinformatics and statistical tools. Furthermore, the deregulation of PRKACA expression in GC and CRC was investigated using correlative and regression analyses. Results: The results showed that PRKACA expression subsets were enriched for gene targets of chemotherapeutics, tyrosine kinase, and β-adrenergic inhibitors. Moreover, high PRKACA expression was associated with adverse clinicopathological and genomic features of GC and CRC. Gene Ontology Enrichment Analysis also showed that PRKACA-high subsets of the GI cancers were enriched for the biological and molecular functions that are associated with cell motility, invasion, and metastasis but not cell proliferation. Finally, multiple regression analyses identified multiple methylation loci, transcription factors, miRNA species, and PRKACA copy number changes that deregulated PRKACA expression in GC and CRC. Conclusions: This study has identified potential predictive and clinicopathological roles for PRKACA expression in GI cancers and has added to the growing body of knowledge on the deregulation of PRKACA in cancer. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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30 pages, 18265 KiB  
Article
Oncogenic Potential of Replication Factor C Subunit 4: Correlations with Tumor Progression and Assessment of Potential Inhibitors
by Muhammad Alaa Eldeen, Farag Mamdouh, Waleed K. Abdulsahib, Refaat A. Eid, Ahmad A. Alhanshani, Ayed A. Shati, Youssef A. Alqahtani, Mohammed A. Alshehri, Mohamed Samir A. Zaki, Mohamed A. Soltan and Ahmed E. Noreldin
Pharmaceuticals 2024, 17(2), 152; https://doi.org/10.3390/ph17020152 - 23 Jan 2024
Cited by 4 | Viewed by 2403
Abstract
Replication Factor C Subunit 4 (RFC4), an oncogene implicated in many human cancers, has yet to be extensively studied in many cancer types to determine its expression patterns and tumor tissue function. Various bioinformatics tools were used to analyze RFC4 as a potential [...] Read more.
Replication Factor C Subunit 4 (RFC4), an oncogene implicated in many human cancers, has yet to be extensively studied in many cancer types to determine its expression patterns and tumor tissue function. Various bioinformatics tools were used to analyze RFC4 as a potential oncogene and therapeutic target across many cancers. We first examined RFC4 expression levels in several human tumor types to determine relationships with tumor grade, stage, metastasis, and patient survival. We also examined RFC4’s genetic changes, epigenetic methylation, and effect on tumor microenvironment (TME) immune cell infiltration. We also analyzed RFC4’s connections with immunological checkpoints to identify potential molecular pathways involved in carcinogenesis. Our findings show that RFC4 is upregulated in several tumor types and associated with poor prognoses in many human cancers. This study shows that RFC4 significantly affects the tumor immunological microenvironment, specifically immune cell populations. Finally, we screened for RFC4-inhibiting pharmacological compounds with anti-cancer potential. This study fully elucidates RFC4’s carcinogenic activities, emphasizing its potential as a prognostic biomarker and a target for anti-cancer therapy. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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28 pages, 5796 KiB  
Article
N-Substituted 2-(Benzenosulfonyl)-1-Carbotioamide Derivatives Exert Antimicrobial and Cytotoxic Effects via Aldehyde Dehydrogenase Pathway: Synthesis, In Silico and In Vitro Studies
by Lucja Walczak-Nowicka, Anna Biernasiuk, Wojciech Ziemichód, Zbigniew Karczmarzyk, Mateusz Kwaśnik, Paweł Kozyra, Waldemar Wysocki, Agnieszka Stenzel-Bembenek, Dorota Kowalczuk, Mariola Herbet and Monika Pitucha
Pharmaceuticals 2023, 16(12), 1706; https://doi.org/10.3390/ph16121706 - 8 Dec 2023
Cited by 1 | Viewed by 1519
Abstract
A series of N-Substituted 2-(benzenosulfonyl)-1-carbotioamide derivatives (WZ1–WZ4) were synthesized and characterized using spectral methods. A comprehensive activity study was performed for each compound. All compounds were tested for antibacterial activity. Moreover, in silico studies were carried out to determine the anticancer potential of [...] Read more.
A series of N-Substituted 2-(benzenosulfonyl)-1-carbotioamide derivatives (WZ1–WZ4) were synthesized and characterized using spectral methods. A comprehensive activity study was performed for each compound. All compounds were tested for antibacterial activity. Moreover, in silico studies were carried out to determine the anticancer potential of the designed WZ1–WZ4 ligands. Based on molecular docking, aldehyde dehydrogenase was selected as a molecular target. The obtained data were compared with experimental data in vitro tests. Novel hybrids of the thiosemicarbazide scaffold and sulfonyl groups may have promising anticancer activity via the aldehyde dehydrogenase pathway. The best candidate for further studies appears to be WZ2, due to its superior selectivity in comparison to the other tested compounds. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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Review

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16 pages, 988 KiB  
Review
AMPA Receptor Modulation in the Treatment of High-Grade Glioma: Translating Good Science into Better Outcomes
by Daniel P. Radin
Pharmaceuticals 2025, 18(3), 384; https://doi.org/10.3390/ph18030384 - 8 Mar 2025
Viewed by 889
Abstract
Glioblastoma (GB) treatment, despite consisting of surgical resection paired with radiation, temozolomide chemotherapy and tumor-treating fields, yields a median survival of 15–20 months. One of the more recently appreciated hallmarks of GB aggressiveness is the co-opting of neurotransmitter signaling mechanisms that normally sustain [...] Read more.
Glioblastoma (GB) treatment, despite consisting of surgical resection paired with radiation, temozolomide chemotherapy and tumor-treating fields, yields a median survival of 15–20 months. One of the more recently appreciated hallmarks of GB aggressiveness is the co-opting of neurotransmitter signaling mechanisms that normally sustain excitatory synaptic communication in the CNS. AMPA-glutamate receptor (AMPAR) signaling governs the majority of excitatory synaptic activity in the mammalian brain. AMPAR activation in glioma cells activates cellular pathways that enhance proliferation and invasion and confer resistance to approved GB therapeutics. In addition, this review places a specific emphasis on discussing the redefined GB cytoarchitecture that consists of neuron-to-glioma cell synapses, whose oncogenic activity is driven by AMPAR activation on glioma cells, and the discovery of tumor microtubes, which propagate calcium signals throughout the tumor network in order to enhance resistance to complete surgical resection and radiotherapy. These new discoveries notwithstanding, some evidence suggests that AMPAR activation can produce excitotoxicity in tumor cells. This disparity warrants a closer examination at how AMPAR modulation can be leveraged to produce more durable outcomes in the treatment of GB and tumors in peripheral organs that express AMPAR. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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12 pages, 1046 KiB  
Review
Entecavir: A Review and Considerations for Its Application in Oncology
by Tânia Lourenço and Nuno Vale
Pharmaceuticals 2023, 16(11), 1603; https://doi.org/10.3390/ph16111603 - 14 Nov 2023
Cited by 5 | Viewed by 3661
Abstract
Entecavir (ETV) is a drug used as a first-line treatment for chronic hepatitis B (CHB) virus infection because it is a guanosine nucleoside analogue with activity against the hepatitis B virus polymerase. The ETV dosage can range from 0.5 mg to 1 mg [...] Read more.
Entecavir (ETV) is a drug used as a first-line treatment for chronic hepatitis B (CHB) virus infection because it is a guanosine nucleoside analogue with activity against the hepatitis B virus polymerase. The ETV dosage can range from 0.5 mg to 1 mg once a day and the most common side effects include headache, insomnia, fatigue, dizziness, somnolence, vomiting, diarrhea, nausea, dyspepsia, and increased liver enzyme levels. In addition to its conventional use, ETV acts as an inhibitor of lysine-specific demethylase 5B (KDM5B), an enzyme that is overexpressed in breast, lung, skin, liver, and prostate tumors and is involved in the hormonal response, stem cell regeneration, genomic stability, cell proliferation, and differentiation. The KDM5B enzyme acts as a transcriptional repressor in tumor suppressor genes, silencing them, and its overexpression leads to drug resistance in certain tumor types. Furthermore, the literature suggests that KDM5B activates the PI3K/AKT signaling pathway, while reducing KDM5B expression decreases AKT signaling, resulting in decreased tumor cell proliferation. In silico studies have demonstrated that ETV can inhibit tumor cell proliferation and induce apoptosis by reducing KDM5B expression. ETV also appears to inhibit PARP-1, has a high genetic barrier, reducing the chance of resistance development, and can also prevent the reactivation of the hepatitis B virus in cancer patients, which have proven to be significant advantages regarding its use as a repurposed drug in oncology. Therefore, ETV holds promise beyond its original therapeutic indication. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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