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Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition

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

Deadline for manuscript submissions: 20 January 2026 | Viewed by 7598

Special Issue Editor

Dr. Bernhard Biersack

E-Mail Website
Guest Editor
Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany
Interests: medicinal chemistry; natural products; multi-component reactions; metal-based drugs; antibiotics and antimycotics; anticancer drugs; antiparasitic drugs; antiviral drugs
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Special Issue Information

Dear Colleagues,

The development of efficient and well-tolerated anticancer drugs is one of the main healthcare challenges of the century, with rising numbers of cancer patients worldwide. The close correspondence of clinicians, tumor biologists and medicinal chemists is mandatory for the successful establishment of new cancer treatments. Small-molecule protein binders and enzyme inhibitors, natural products, DNA-targeting alkylating agents and metal complexes form the main part of the current arsenal of anticancer drugs, which can serve as starting points for the development of new compounds with improved activity, bioavailability and potential to overcome drug resistance. Repurposed drugs and cost-effective new compounds obtained from multi-component reactions or few-step syntheses can become broadly available anticancer drugs. Computer-aided drug design contributes to the optimisation of existing drugs, as well as the identification of the first-generation inhibitors of new cancer targets. Sophisticated formulation systems improve pharmacokinetics and the tumor targeting properties of anticancer drugs. Recent drug research efforts aim at cancer epigenetics, cancer stem-like cells, tumor microenvironment and immunology. This Special Issue intends to showcase the current efforts on anticancer drug design and development. Original research articles, review articles, and short communications within (but not restricted to) the described research fields are welcome.

Dr. Bernhard Biersack
Guest Editor

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Keywords

  • cancer
  • anticancer drugs
  • drug design
  • targeted therapy
  • immunotherapy
  • molecular target
  • molecular mechanism
  • drug resistance

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Published Papers (6 papers)

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Research

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30 pages, 5633 KiB  
Article
New 1,2,4-Triazole Derivatives with a N-Mannich Base Structure Based on a 4,6-Dimethylpyridine Scaffold as Anticancer Agents: Design, Synthesis, Biological Evaluation, and Molecular Modeling
by Piotr Świątek, Teresa Glomb, Benita Wiatrak, Paulina Nowotarska, Tomasz Gębarowski, Kamil Wojtkowiak, Aneta Jezierska and Małgorzata Strzelecka
Int. J. Mol. Sci. 2025, 26(14), 6572; https://doi.org/10.3390/ijms26146572 - 8 Jul 2025
Viewed by 242
Abstract
A series of novel N-Mannich bases derived from a dimethylpyridine–1,2,4-triazole hybrid was synthesized and evaluated in vitro for cytotoxic activity on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, and HT-29). Compound 6 bearing a phenyl group at the N-4 position [...] Read more.
A series of novel N-Mannich bases derived from a dimethylpyridine–1,2,4-triazole hybrid was synthesized and evaluated in vitro for cytotoxic activity on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, and HT-29). Compound 6 bearing a phenyl group at the N-4 position and a 4-methylphenyl piperazine moiety at the N-2 position of the 1,2,4-triazole-3-thione scaffold exerted good cytotoxic activities on EPG and Caco-2 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal colonic epithelial cells (CCD 841 CoTr). Further evaluation revealed the good ability of compound 6 to inhibit the efflux function of P-glycoprotein in P-gp-expressing cell lines (HT-29, LoVo, and LoVo/Dx). Moreover, compound 6 induced apoptotic cell death through a significant increase in the caspase-3 and p53 protein levels in HT-29 cells. Finally, the molecular docking method was applied to explain our experimental findings. The molecular modeling study based on Density Functional Theory (DFT) and the Quantum Theory of Atoms in Molecules (QTAIM) analysis provided insight into the geometric and electronic structure properties of the compounds. Full article
(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)
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17 pages, 1966 KiB  
Article
Development of INER-PP-F11N as the Peptide-Radionuclide Conjugate Drug Against CCK2 Receptor-Overexpressing Tumors
by Ming-Cheng Chang, Chun-Tang Chen, Ping-Fang Chiang, I-Chung Tang, Cheng-Liang Peng, Yuh-Feng Wang, Yi-Jou Tai and Ying-Cheng Chiang
Int. J. Mol. Sci. 2025, 26(14), 6565; https://doi.org/10.3390/ijms26146565 - 8 Jul 2025
Viewed by 284
Abstract
This work aimed to evaluate two albumin affinity structure-containing peptide-radionuclide conjugate drugs, INER-PP-F11N-1 and INER-PP-F11N-2, for the diagnosis/treatment of cholecystokinin receptor subtype 2 (CCK2R)-overexpressing cancers. We developed In-111- and Lu-177-labeled INER-PP-F11N radiopharmaceuticals and compared them with the current PP-F11N to investigate metabolic stability, [...] Read more.
This work aimed to evaluate two albumin affinity structure-containing peptide-radionuclide conjugate drugs, INER-PP-F11N-1 and INER-PP-F11N-2, for the diagnosis/treatment of cholecystokinin receptor subtype 2 (CCK2R)-overexpressing cancers. We developed In-111- and Lu-177-labeled INER-PP-F11N radiopharmaceuticals and compared them with the current PP-F11N to investigate metabolic stability, biodistribution, SPECT/CT imaging, and therapeutic responses in CCK2R-expressing tumor xenograft mice. The metabolic stability of [111In]In/[177Lu]Lu-INER-PP-F11N remained above 90% for up to 144 h after labeling, indicating that the compound is highly stable under in vitro conditions. INER-PP-F11N showed 27% and 11% higher cellular uptake and internalization than PP-F11N, respectively. In vivo SPECT/CT imaging confirmed that INER-PP-F11N could accumulate at the tumor site of mice 24 h after receiving the two radiopharmaceutical agents. Biodistribution analysis revealed a significantly greater tumor uptake and reduced accumulation of INER-PP-F11N in the kidneys compared with PP-F11N. Furthermore, INER-PP-F11N significantly inhibited the growth of the CCK2R-overexpressing tumors in mice. The INER-PP-F11N radiopharmaceutical was superior as a theragnostic agent compared with the current PP-F11N. Our study suggests that INER-PP-F11N may be an innovative radiopharmaceutical agent for CCK2R-overexpressing tumors. Full article
(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)
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24 pages, 5303 KiB  
Article
Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells
by Patrycja Wińska, Monika Wielechowska, Łukasz Milewski, Paweł Siedlecki and Edyta Łukowska-Chojnacka
Int. J. Mol. Sci. 2025, 26(12), 5897; https://doi.org/10.3390/ijms26125897 - 19 Jun 2025
Viewed by 418
Abstract
Inhibition of CK2 and/or PIM-1 kinases has been shown to induce apoptosis in a variety of cancer cell lines, underscoring their potential as valuable targets in anti-cancer drug development. In this study, a series of N-substituted derivatives of 4,5,6,7-tetrabromo-1H-benzimidazole, including [...] Read more.
Inhibition of CK2 and/or PIM-1 kinases has been shown to induce apoptosis in a variety of cancer cell lines, underscoring their potential as valuable targets in anti-cancer drug development. In this study, a series of N-substituted derivatives of 4,5,6,7-tetrabromo-1H-benzimidazole, including 2-oxopropyl/2-oxobutyl substituents and their respective hydroxyl analogues, were synthesized and evaluated for anti-cancer activity. The compounds’ ability to inhibit CK2α and PIM-1 kinases was assessed through enzymatic assays, complemented by comprehensive in silico enzyme–substrate docking analyses. Cytotoxicity was evaluated using the MTT assay in human cancer cell lines—including acute lymphoblastic leukemia (CCRF-CEM) and breast cancer (MCF-7, MDA-MB-231)—as well as in normal Vero cells. Apoptosis induction in the two most responsive cell lines (CCRF-CEM and MCF-7) was further examined using flow cytometry-based assays, including annexin V binding, mitochondrial membrane potential disruption, caspase-3 activation, and cell cycle analysis. Intracellular inhibition of CK2 and PIM-1 kinases was confirmed in CCRF-CEM and MCF-7 cells using Western blot and phospho-flow cytometry. Among the synthesized compounds, we identified a novel TBBi derivative exhibiting pronounced pro-apoptotic activity and the ability to inhibit PIM-1 kinase intracellularly. These findings support the hypothesis that PIM-1 kinase represents a promising molecular target for the treatment of leukemia. Full article
(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)
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21 pages, 13070 KiB  
Article
MK-8776 and Olaparib Combination Acts Synergistically in Hepatocellular Carcinoma Cells, Demonstrating Lack of Adverse Effects on Liver Tissues in Ovarian Cancer PDX Model
by Wiktoria Bębenek, Arkadiusz Gajek, Agnieszka Marczak, Jan Malý, Jiří Smejkal, Małgorzata Statkiewicz, Natalia Rusetska, Magdalena Bryś and Aneta Rogalska
Int. J. Mol. Sci. 2025, 26(2), 834; https://doi.org/10.3390/ijms26020834 - 20 Jan 2025
Viewed by 3246
Abstract
Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the [...] Read more.
Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles. Full article
(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)
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13 pages, 4539 KiB  
Article
Synergistic Enhancement of Antitumor Effects by Combining Abemaciclib with Desipramine
by Yan Li, Yeojin Sung, Young Eun Choi, Yongdoo Choi and Sung-Ho Goh
Int. J. Mol. Sci. 2024, 25(13), 7407; https://doi.org/10.3390/ijms25137407 - 5 Jul 2024
Viewed by 1760
Abstract
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various [...] Read more.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors. Full article
(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)
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Review

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26 pages, 440 KiB  
Review
Immune Checkpoint Inhibitors in Clear Cell Renal Cell Carcinoma (ccRCC)
by Jacek Rysz, Janusz Ławiński, Beata Franczyk and Anna Gluba-Sagr
Int. J. Mol. Sci. 2025, 26(12), 5577; https://doi.org/10.3390/ijms26125577 - 11 Jun 2025
Viewed by 653
Abstract
Renal cell carcinoma (RCC) accounts for about 403,000 new cases and 175,000 deaths worldwide each year. Clear cell RCC (ccRCC), the most prevalent subtype, is often driven by genetic mutations, such as VHL inactivation, leading to angiogenesis and immune escape. Immune checkpoint inhibitors [...] Read more.
Renal cell carcinoma (RCC) accounts for about 403,000 new cases and 175,000 deaths worldwide each year. Clear cell RCC (ccRCC), the most prevalent subtype, is often driven by genetic mutations, such as VHL inactivation, leading to angiogenesis and immune escape. Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed treatment paradigms, yet therapeutic resistance remains a critical challenge. The immunosuppressive nature of the tumor microenvironment (TME) in ccRCC plays a central role in limiting ICI efficacy. Emerging strategies aim to overcome resistance by targeting key components of the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and cytokine signaling. Agents such as nivolumab, pembrolizumab, and ipilimumab have demonstrated the ability to restore T-cell activity and mitigate immune suppression, offering clinical benefit in metastatic ccRCC. However, response rates vary, highlighting the need for rational combination therapies. ICIs combined with VEGF inhibitors have shown promising outcomes in clinical trials, and novel regimens continue to be explored. Risk stratification and personalized treatment selection are increasingly important as the therapeutic landscape evolves. This review synthesizes current advances in immunotherapy for ccRCC, with a focus on mechanisms of resistance and innovative strategies to enhance immune responsiveness. A deeper understanding of TME modulation and strategic combination approaches is essential to improve survival and quality of life for patients with advanced ccRCC. Full article
(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)
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