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Cancers
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Cancer Drug Discovery and Development
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Cancer Drug Discovery and Development

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Drug Development".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 6017

Special Issue Editors

Dr. Gary Piazza

E-Mail Website
Guest Editor
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
Interests: RAS; β-catenin; phosphodiesterase; cGMP; cancer
Prof. Dr. Zhe-Sheng (Jason) Chen

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
Interests: drug resistance; ABC transporter; tyrosine kinase inhibitor; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer drug discovery is vital as it leads to the development of effective treatments that specifically target cancer cells while minimizing harm to healthy cells. The discovery of new drugs offers hope for greater efficacy and potential in combating drug resistance.  

This Special Issue aims to collect original research articles or reviews relating to the discovery and development of novel anticancer drugs, including the identification or validation of novel molecular targets, drug design and development, strategies for enhancing or broadening the activity of immunotherapy, preclinical and clinical trials, and personalized medicine approaches.  This Special Issue will highlight the latest research findings on molecular mechanisms underlying cancer progression and present innovative strategies to target specific cancer types or pathways or to combat resistance. Studies on the role of emerging technologies, such as artificial intelligence and high-throughput screening, in accelerating the drug discovery process are also welcome.

We hope that cancer research experts from around the world will share their knowledge and insights into cancer drug discovery and development. This Special Issue will also provide a platform for discussing the challenges faced in drug resistance and toxicity, the need for more efficient drug delivery systems for cancer treatment, as well as for exploring potential solutions and future directions for cancer research.

Dr. Gary Piazza
Prof. Dr. Zhe-Sheng (Jason) Chen
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 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. Cancers 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 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

  • signal transduction inhibitors
  • small-molecule inhibitors
  • antibodies
  • PROTOC
  • immunotherapy
  • medicinal chemistry
  • chemical optimization
  • high-throughput screening

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Published Papers (4 papers)

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Research

12 pages, 3001 KiB  
Article
The Target Therapy Hyperbole: “KRAS (p.G12C)”—The Simplification of a Complex Biological Problem
by Massimiliano Chetta, Anna Basile, Marina Tarsitano, Maria Rivieccio, Maria Oro, Nazzareno Capitanio, Nenad Bukvic, Manuela Priolo and Alessandra Rosati
Cancers 2024, 16(13), 2389; https://doi.org/10.3390/cancers16132389 - 28 Jun 2024
Viewed by 1015
Abstract
Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene variations are linked to the development of numerous cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The lack of typical drug-binding sites has long hampered the discovery of [...] Read more.
Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene variations are linked to the development of numerous cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The lack of typical drug-binding sites has long hampered the discovery of therapeutic drugs targeting KRAS. Since “CodeBreaK 100” demonstrated Sotorasib’s early safety and efficacy and led to its approval, especially in the treatment of non-small cell lung cancer (NSCLC), the subsequent identification of specific inhibitors for the p.G12C mutation has offered hope. However, the CodeBreaK 200 study found no significant difference in overall survival (OS) between patients treated with Docetaxel and Sotorasib (AMG 510), adding another degree of complexity to this ongoing challenge. The current study compares the three-dimensional structures of the two major KRAS isoforms, KRAS4A and KRAS4B. It also investigates the probable structural changes caused by the three major mutations (p.G12C, p.G12D, and p.G12V) within Sotorasib’s pocket domain. The computational analysis demonstrates that the wild-type and mutant isoforms have distinct aggregation propensities, resulting in the creation of alternate oligomeric configurations. This study highlights the increased complexity of the biological issue of using KRAS as a therapeutic target. The present study stresses the need for a better understanding of the structural dynamics of KRAS and its mutations to design more effective therapeutic approaches. It also emphasizes the potential of computational approaches to shed light on the complicated molecular pathways that drive KRAS-mediated oncogenesis. This study adds to the ongoing efforts to address the therapeutic hurdles presented by KRAS in cancer treatment. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development)
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24 pages, 6730 KiB  
Article
N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents
by Noha Mostafa, Po-Jen Chen, Sarah S. Darwish, Yu-Chieh Su, Ming-Hua Shiao, Gary A. Piazza, Ashraf H. Abadi, Matthias Engel and Mohammad Abdel-Halim
Cancers 2024, 16(11), 2033; https://doi.org/10.3390/cancers16112033 - 27 May 2024
Viewed by 1268
Abstract
Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective [...] Read more.
Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development)
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18 pages, 6422 KiB  
Article
Proguanil Suppresses Breast Tumor Growth In Vitro and In Vivo by Inducing Apoptosis via Mitochondrial Dysfunction
by Nehal Gupta, Marina Curcic and Sanjay K. Srivastava
Cancers 2024, 16(5), 872; https://doi.org/10.3390/cancers16050872 - 22 Feb 2024
Viewed by 1381
Abstract
Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects [...] Read more.
Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil’s anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development)
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15 pages, 1093 KiB  
Article
First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors
by Anna R. Schreiber, Jodi A. Kagihara, Bradley R. Corr, S. Lindsey Davis, Christopher Lieu, Sunnie S. Kim, Antonio Jimeno, D. Ross Camidge, Jud Williams, Amy M. Heim, Anne Martin, John A. DeMattei, Nisha Holay, Todd A. Triplett, S. Gail Eckhardt, Kevin Litwiler, James Winkler, Anthony D. Piscopio and Jennifer R. Diamond
Cancers 2024, 16(1), 91; https://doi.org/10.3390/cancers16010091 - 23 Dec 2023
Cited by 3 | Viewed by 1543
Abstract
(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the [...] Read more.
(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11–447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development)
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