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Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential

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

Deadline for manuscript submissions: 25 July 2026 | Viewed by 7563

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Dr. Dmytro Khylyuk

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Chair and Department of Organic Chemistry, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland
Interests: anticancer drugs; molecular docking and dynamics; 4-thiazolidinones

Special Issue Information

Dear Colleagues,

Despite significant advances in anticancer agents, cancer remains a major medical challenge due to the complexity and heterogeneity of tumor cells, as well as their capacity to develop treatment resistance. Researchers are therefore exploring novel approaches to create more effective and safer drugs, with a particularly promising strategy focused on hybrid molecules that combine multiple mechanisms of action or enhance existing therapies.

Developing hybrid anticancer agents entails combining multiple pharmacophores and privileged scaffolds into a single molecule to overcome drug resistance, enhance cytotoxicity against cancer cells, and improve selectivity. Such strategies aim to achieve a comprehensive anticancer effect by simultaneously targeting two or more key pathogenic pathways.

This Special Issue aims to showcase the latest developments in hybrid anticancer drugs, including innovative synthetic methods, therapeutic potential, and mechanistic insights. We especially welcome submissions featuring targeted drug design aimed at influencing specific pathogenetic pathways, as well as research presenting both in vitro and in vivo findings and robust in silico evidence supporting cytotoxic activity and predicted mechanisms of action.

We invite original research and review articles that detail novel approaches, discuss emerging trends, and propose pathways for future discovery and development of new, more effective anticancer drugs.

Dr. Dmytro Khylyuk
Guest Editor

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Keywords

drug design
molecular hybrids
anticancer agents
privileged scaffold
multiple mechanisms of action

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Published Papers (6 papers)

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Research

26 pages, 2023 KB

Open AccessArticle

Development and Application of an UPLC–MS/MS Method for Simultaneous Quantification of Abemaciclib and Tamoxifen with Their Active Metabolites in Rat Plasma: Application to a Pharmacokinetic Study

by Yahya Alshehri, Abdulrhman Al-Majed, Ahmad Obaidullah, Yousef Bin Jardan, Ahmed Bakheit and Mohamed Hefnawy

Pharmaceuticals 2026, 19(5), 795; https://doi.org/10.3390/ph19050795 (registering DOI) - 19 May 2026

Abstract

Background: Abemaciclib (ABM) in combination with tamoxifen (TAM) is an extremely significant treatment regimen for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. It is approved for patients to reduce the risk of cancer recurrence. A bioanalytical method for the simultaneous determination of this new anti-breast cancer combination and its pharmacokinetic application has not yet been reported. Methods: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) method was developed for quantifying ABM, TAM, and its metabolites, including abemaciclib active metabolites M2, M18, and M20 and tamoxifen active metabolite N-desmethyl tamoxifen (NDTAM), in rat plasma using econazole as the internal standard (IS). Chromatographic separation was achieved on a Kinetex C18 column (100 × 2.1 mm ID, 2.6 µm) using gradient elution with 5 mM ammonium formate in water (eluent A) and 5 mM ammonium formate in water/methanol (1:9, v/v, eluent B) at a flow rate of 0.4 mL/min. Detection was performed on a TSQ Fortis Plus mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization. Results: The developed method was validated according to the guidance of the FDA. Linearity in rat plasma (ng/mL) was achieved from 1 to 1000 for ABM, TAM, and M20; 3 to 1000 for M2; 5 to 500 for M18; and 1 to 500 for NDTAM; with correlation coefficients ranging from 0.9991 to 0.9931 for all analytes using a weighting factor of 1/X². The lower limit of detection (LLOD) ranged between 0.3 and 1.5 ng/mL for all drugs. The accuracy ranged from 96 to 108% and the precision was less than 7.6% RSD for all analytes. For the first time, the newly developed approach was effectively used in a pharmacokinetic study on the simultaneous oral administration of ABM and TAM in rats that received 30.0 mg/kg of ABM and 8.0 mg/kg of TAM. Conclusions: To the best of our knowledge, this is the first reported UPLC–MS/MS method for the assay of ABM, TAM, and its active metabolites in plasma. This method offers a bioanalytical tool for assessing the pharmacokinetics of ABM and TAM. Therefore, this study makes a definite significant contribution to the field of bioanalytical research. Further validation in human plasma is required for future clinical or therapeutic drug monitoring applications, as the approach was developed in an animal model. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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32 pages, 5477 KB

Open AccessArticle

Novel Adenine–Hydrazone Hybrids Against Human Lung Adenocarcinoma (A549): Design, Synthesis, Cellular Mechanistic Investigation and Molecular Docking Studies

by Emre Menteşe, Nedime Çalışkan, Didem Aksu, Mustafa Emirik, Adem Güner and Fatih Yılmaz

Pharmaceuticals 2026, 19(3), 474; https://doi.org/10.3390/ph19030474 - 13 Mar 2026

Viewed by 522

Abstract

Background/Objectives: Adenine derivatives are promising anticancer scaffolds, but their cellular mechanisms remain unclear. This study aimed to synthesize adenine–hydrazone hybrids and evaluate their cytotoxic effects in human lung adenocarcinoma (A549) cells. Methods: A series of adenine–hydrazone compounds (3a–r) was synthesized and tested for cytotoxicity in A549 and MRC-5 cells. Selected compounds were further analyzed for LDH release, oxidative stress markers, ROS production, mitochondrial membrane potential, cell-cycle distribution, apoptosis, and in silico docking against VEGFR2, ALK5, and EGFR. Results: Compounds with electron-withdrawing or donor–acceptor substituents showed the highest cytotoxicity, while halogenated and methoxy analogs were moderately active. Among the synthesized derivatives, 4F-substituted derivatives (3c) showed more activity than 2F- and 3F-substituted ones (3a and 3b). 4F- and 3Br-substituted derivatives (3f) showed more activity than only 4F-substituted ones (3c). 4-Nitro-substituted derivative (3i) showed more activity than 4F- (3c), 4Cl- (3d) and 4OMe- (3h) derivatives. Trimethoxy-substituted derivative (3l) showed more activity than di- and mono-substituted methoxy derivatives (3g, 3h, 3j and 3k). Among the salicyl aldehydederivatives (3m–r), 4-N(et)₂-substituted derivative (3r) showed more activity than non-substituted (3m), 5Br-(3n), 5Cl-(3o), 5Me (3p) and 3OCH₃ (3q) derivatives. Treatment induced oxidative stress, mitochondrial depolarization, Sub-G1 cell-cycle accumulation, and apoptosis. Docking studies indicated strong binding to VEGFR2 and ALK5, suggesting dual inhibition as a potential mechanism. Conclusions: Adenine–hydrazone derivatives exert substituent-dependent anticancer effects by inducing redox imbalance-associated mitochondrial dysfunction and regulated cell death. These results highlight their potential as lead structures for lung cancer therapy. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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48 pages, 17329 KB

Open AccessArticle

Novel Active Homo-Aza (Lactam) Steroidal Antimetabolites for the Treatment of Human Pancreatic and Colorectal Cancer

by Konstantinos E. Alifieris, Panagiotis Dalezis, Sofia Sagredou, Ioanna A. Anastasiou, Maria Deligiorgi, Christos Siokatas, Nikolaos Spanakis, Konstantinos Almpanakis, Maria Voura, Kyriakos Orfanakos, Mihalis Panayiotidis, Vasiliki Sarli and Dimitrios T. Trafalis

Pharmaceuticals 2026, 19(2), 331; https://doi.org/10.3390/ph19020331 - 17 Feb 2026

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Abstract

Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Steroidal conjugation offers an approach to enhance selectivity and toxicokinetics. Methods: Five novel hybrid homo-aza (lactam) steroidal antimetabolites (GE23, CS18, CS23, KA44, MV16) were synthesized and tested against three pancreatic and four colorectal carcinoma cell lines with distinct molecular characteristics. Antiproliferative activity (MTT), apoptosis (Annexin V/PI), and cell cycle effects were assessed. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibition was examined via molecular docking, Western blot, and enzymatic assays. Correlations between docking binding scores (DBS) and biological data were analyzed, and effects were compared with reference drugs (5-FU, MTX, GEM). Results: CS23, CS18, and KA44 exhibited the most potent cytostatic activity (mean GI₅₀ 10–80 µM). CS23 also induced high cytocidal effects, strong apoptosis (40% at 72 h), and G1/S arrest. Moreover, docking predicted the high binding affinity of CS23 for both TS (−11.2 kcal/mol) and DHFR (−11.5 kcal/mol), which was validated by Western blot and enzymatic inhibition (IC₅₀ ≈ 20 nM). Correlation analyses showed significant relationships between hybrid steroidal antimetabolites’ cytostatic efficacy and DBS for TS (r = −0.75) and DHFR (r = −0.76), and combined DBS values predicted growth inhibition (r = −0.81, p < 0.01). No simple, universal correlation with single mutations of KRAS, BRAF, PI3K, or TP53 was found. Conclusions: Lactam steroidal antimetabolite hybrids, particularly CS23, act as dual TS/DHFR inhibitors, inducing apoptosis and cell cycle arrest with improved selectivity. Their strong in silico–in vitro concordance provides a compelling preclinical rationale for further evaluation of steroidal antimetabolites as next-generation therapeutics for resistant gastrointestinal malignancies. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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33 pages, 4483 KB

Open AccessArticle

Evaluation of Antiproliferative Activity and Molecular Modeling Studies of Some Novel Benzimidazolone-Bridged Hybrid Compounds

by Okan Güven, Emre Menteşe, Fatih Yılmaz, Adem Güner, Mustafa Emirik and Nedime Çalışkan

Pharmaceuticals 2025, 18(12), 1899; https://doi.org/10.3390/ph18121899 - 17 Dec 2025

Cited by 3 | Viewed by 976

Abstract

Background/Objectives: Cancer is among the leading causes of mortality worldwide. In 2022 alone, the global cancer death toll stood at 9.74 million. Projections indicate that this figure will rise to 10.4 million by 2025. Methods: A new series of benzimidazolone-bridged hybrid compounds containing thiophene, furan, oxadiazole, piperazine, and coumarin moieties was synthesized and structurally characterized by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis. Their cytotoxic effects were evaluated by MTT assay against human lung (A549), human breast (MCF-7), and human cervical (HeLa) cancer cell lines, and the non-cancerous HEK293 cell line after 48 h exposure over a concentration range of 0.5–250 µM. IC₅₀ values were determined, and Selectivity Indexes (SI) were calculated using HEK293 as the reference normal cell line. Molecular docking studies were carried out using the Glide XP protocol against VEGFR2 (PDB ID: 4ASD) and CDK4–Cyclin D3 (PDB ID: 7SJ3), with sorafenib and abemaciclib as reference inhibitors. Results: The results of anticancer activity were compared with doxorubicin (IC₅₀ ± SD (µM)/SI: 4.3 ± 0.2/1.20 for A549, 6.4 ± 0.37/0.77 for MCF-7, 3.4 ± 0.19/1.54 for HeLa), a drug used for cancer chemotherapy. The structures of the newly synthesized hybrid compounds were identified by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis data. These hybrid compounds represent a promising class of anticancer agents. Several compounds demonstrated marked and concentration-dependent cytotoxicity across all cancer cell lines, with HeLa cells showing the highest overall sensitivity. The introduction of an oxadiazole ring (compound 7) and coumarin substituents (compounds 12b–12d) markedly improved anticancer activity and selectivity, yielding low-micromolar IC₅₀ values in HeLa cells (10.6–13.6 µM) and high Selectivity Indexes (SI = 2.0–3.63). Compound 6 also exhibited balanced potency across A549, MCF-7, and HeLa cells (IC₅₀ = 28.3–31.2 µM) with SI values ≥ 2.0. Compound 9 showed strong cytotoxicity across all cancer cell lines; its moderate SI values indicate lower discrimination between malignant and non-malignant cells. Taken together, these findings identified compounds 7, 12b–12d, 6, and 12c as the most promising benzimidazolone-based candidates, displaying both potent cytotoxicity and favorable selectivity over non-malignant HEK293 cells. Conclusions: Among the synthesized molecules, the oxadiazole derivative (7) and the coumarin-based hybrids (12b–12d) exhibited the strongest combination of cytotoxic activity and selectivity, reflected by their low IC₅₀ values and high SI ratios. Notably, compound 12c combined strong biological activity with the highest predicted VEGFR2 affinity in the series, highlighting it as a particularly promising scaffold. While compound 9 exhibited excellent docking scores toward both VEGFR2 and CDK4, its lower selectivity suggests a need for further structural refinement. Overall, the biological and computational findings converge to identify these benzimidazolone hybrids as credible lead candidates for future anticancer optimization. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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25 pages, 2760 KB

Open AccessArticle

Design and Optimization of Spiro-Isatin-Thiazolidinone Hybrids with Promising Anticancer Activity

by Dmytro Khylyuk, Serhii Holota, Natalia Finiuk, Rostyslav Stoika, Tetyana Rumynska and Roman Lesyk

Pharmaceuticals 2025, 18(10), 1502; https://doi.org/10.3390/ph18101502 - 7 Oct 2025

Viewed by 1036

Abstract

Background: Cancer remains a leading cause of morbidity and mortality worldwide, and current therapies are limited by toxicity, cost, and resistance. Inhibition of the MDM2–p53 interaction is a promising anticancer strategy, as this pathway is frequently dysregulated across tumors. Spiro-isatin-thiazolidinone derivatives have shown diverse biological activities, including anticancer effects, but require optimization to improve potency and selectivity. The aims were to design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids with enhanced cytotoxicity against cancer cells and reduced toxicity toward normal cells. Methods: Derivatives were designed using molecular docking against MDM2, followed by structural optimization. Cytotoxic activity was evaluated in vitro by MTT assays on human and murine cancer cell lines and pseudo-normal cells. Docking and 100 ns molecular dynamics simulations assessed binding stability, while ADMET properties were predicted in silico. Results: Several derivatives exhibited micromolar cytotoxicity, with compound 18 emerging as the most potent and selective candidate (IC₅₀ 6.67–8.37 µM across most cancer lines; >100 µM in HaCaT). Docking showed a strong affinity for MDM2 (−10.16 kcal/mol), comparable to the reference ligand, and stable interactions in simulations. ADMET predictions confirmed good oral bioavailability and moderate acute toxicity, fully compliant with Lipinski’s Rule of Five. Overall, the newly synthesized spiro-isatin-thiazolidinone hybrids, particularly compound 18, demonstrated potent and selective anticancer activity, favorable pharmacokinetic properties and a good toxicity profile. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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15 pages, 1915 KB

Open AccessCommunication

Performance of Imidazoquinoline Glycoconjugate BAIT628 as a TLR7 Agonist Prodrug for Prostate Cancer

by Seyedeh A. Najibi, S. M. Al Muied Pranto, Muhammad Haroon, Amy E. Nielsen and Rock J. Mancini

Pharmaceuticals 2025, 18(6), 804; https://doi.org/10.3390/ph18060804 - 27 May 2025

Cited by 1 | Viewed by 2438

Abstract

Despite broad anti-cancer efficacy as Toll-Like Receptor (TLR) 7/8 agonists, imidazoquinolines remain limited in use via systemic administration or in situ vaccination therapies due to inflammatory toxicity. One approach to address this challenge involves better targeting the action of imidazoquinolines by caging them as glycoconjugate prodrugs. Within cancer cells, imidazoquinoline glycoconjugates are activated by hydrolases prior to efflux by ABC transport proteins, where they then elicit tumoricidal effects from the assistance of bystander immune cells, such as tumor-infiltrating lymphocytes and associated macrophages, in local proximity. While this concept of Bystander-Assisted ImmunoTherapy (BAIT) has been established at a molecular level in vitro, tolerability or efficacy of BAIT has not been reported in vivo. Here, we evaluate the MTD and tumor growth delay efficacy of a lead BAIT prodrug (BAIT628) in a male C57BL/6 mouse TRAMP-C2 prostate cancer model to further establish this methodology. Overall, we find that systemic BAIT628 is well tolerated at over 5-fold the dose-limiting inflammatory toxicity of the parent imidazoquinoline (up to 5 mg/mouse/day I.P. for 10 days). Analyzing serum cytokines reveals that IL-10 production, elicited by the mannoside caging group, likely contributes to the enhanced MTD. Using BAIT628 as an in situ vaccination immunotherapy (seven times over 3 weeks) resulted in significant tumor growth delay and increased survival, both alone and in combination with a murinized α-PD-L1 checkpoint blockade. The tumor histology of tumor-infiltrating immune cell subsets (CD4⁺, CD8⁺, CD11c⁺) reveals significant increases in CD11c⁺ populations, consistent with TLR7/8 agonism. Overall, BAIT628 is well tolerated and exhibits significant efficacy in the TRAMP-C2 model. These results demonstrate how the BAIT approach can optimize imidazoquinolines for in vivo tolerability and subsequent efficacy as cancer immunotherapeutics. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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