Discovering new drug candidates for complex diseases like cancer is a significant challenge in modern drug discovery. Drug repurposing provides a cost-effective and time-efficient strategy to identify existing drugs for novel therapeutic targets. Here, we exploited an integrated in-silico approach to identify repurposed drugs that could inhibit programmed death-ligand 1 (PD-L1). PD-L1 is a crucial protein that plays a pivotal role in immune checkpoint regulation, making it a potential target for cancer treatment. Using a drug repurposing approach, we combined molecular docking and molecular dynamics (MD) simulations to study the binding efficiency of FDA-approved drug molecules targeting PD-L1. From the binding affinities and interaction analysis of the first screening, several molecules emerged as PD-L1 binders. Two of them, Lumacaftor and Vedaprofen, showed appropriate drug profiles and biological activities and stood out as highly potent binding partners of the PD-L1. MD simulation was performed for 500 ns to assess the conformational and stability changes of PD-L1-Lumacaftor and PD-L1-Vedaprofen complexes. The simulations revealed sustained structural integrity and stable binding of both complexes throughout the 500 ns trajectories, supporting their potential as PD-L1 inhibitors. While the findings are promising, they remain computational and require experimental validation to confirm biological efficacy and specificity. This study also emphasizes the role of bioinformatics approaches in drug repurposing that can help in the identification of novel anticancer agents.

Cisplatin is one of effect chemotherapeutic drugs for triple-negative breast cancer (TNBC). However, cisplatin chemoresistance often generate in a notable proportion of TNBC patients, leading therapeutic failure. Thus, identification of key regulatory mechanisms for chemoresistance is important. Here, we aimed to study the functions and regulatory mechanisms of CLEC3B in cisplatin chemoresistance in TNBC.

Colorectal cancer (CRC) is cancer of the colon or bowel. Every year, more than 1.8 million cases of colorectal cancer are reported, with 850,000 deaths. There are several genetic causes of this disease. However, one of the main reasons is the overexpressed KRAS gene that can cause uncontrolled cell division and tumor development. The present study is focused on the identification of potential phytochemicals that can inhibit the KRAS protein from being overexpressed in CRC. For this study, phytochemicals were retrieved from the IMPPAT library, which has 17,967 phytochemical compounds. The compounds were further screened based on the ADMET criteria. The screened compounds were then docked against the KRAS protein using a molecular docking approach, and the binding energies were calculated. Indicating a considerable affinity for interacting with the KRAS protein, it was shown that compound-1 had a binding energy of -9.7 kcal/mol upon analysis. Furthermore, for docking reasons, the anticancer medication fruquintinib, which has been authorized by the FDA, was used as a reference chemical. A binding energy of -9.4 kcal/mol was observed for the reference chemical, as was mentioned before. To find out the reactivity of the selected compound, DFT analysis was performed. The protein-ligand complex was also subjected to molecular dynamics (MD) simulation. Post simulation analysis, such as RMSD, RMSF, Rg, and no of hydrogen bonds, indicated a stable protein-ligand complex.

HER2 overexpression/amplification (HER2+) occurs in approximately 15-20% of breast cancer (BC) and identifies a highly aggressive BC subtype. The cure rate of HER2 + BC has been significantly increased through recent clinical achievements; however, a non-negligible proportion of patients still either fails to respond or acquires resistance to targeted therapies, highlighting the need for novel treatment strategies. As demonstrated in robust preclinical studies, HER2 + BC is considered a neoplastic disease with a peculiar lipogenic phenotype, due to its crucial addiction to an exacerbated need for fatty acids (FAs) produced via FA synthase (FASN), the central lipogenic enzyme required for intracellular de novo FA biosynthesis. FASN is overexpressed/activated in most HER2 + BC cells sustaining their growth, proliferation, and aggressiveness through a reciprocal direct interplay with the HER2-driven oncogenic signaling. Recent evidence shows that rewiring of lipid metabolism in the presence of pharmacological HER2 inhibition impairs FASN up-regulation and activates the compensatory lipid metabolic pathway of FA uptake via the altered expression/activity of the transmembrane CD36 FA transporter. Thus, the latter is emerging as a potentially new and targettable mechanism of resistance to anti-HER2 therapies. Due to the limited availability of drug-like compounds that selectively target CD36, in this study we screened a library of commercial compounds through in silico docking on the crystal structure of the CD36 extracellular domain. We evaluated their chemical-physical, biological and metabolic properties through microscale thermophoresis and molecular dynamics analyses, cell viability assays performed in monotherapy and dual blockade, and gas chromatography-flame ionization detector and BODIPY C16 uptake analyses. Among the best ranked compounds, we selected two promising hits with micromolar affinity for CD36, showing in vitro that they decrease per se the proliferation of HER2 + BC cells resistant to anti-HER2 agents, induce apoptotic effects, significantly reduce FA intracellular internalization, and potentiate the cytotoxic activity of lapatinib, i.e. the most suitable anti-HER2 drug used in in vitro bioassays. Taken together, these findings support that our novel anti-CD36 small molecules should undergo hit-to-lead optimization to prospectively improve the efficacy of anti-HER2 agents in HER2 + BC refractory to targeted therapy.

A series of new uracil derivatives/ursolic acid hybrids were designed and synthesised as potential cytotoxic agents. The uracil, thymine, 6-methyluracil and 2-thiouracil moieties were linked to ursolic acid (1) through alkyl chains of different lengths (either four or six -CH2- units). The cytotoxic activity of the synthesised conjugates was determined using the hormone-dependent breast cancer cell line MCF-7, the triple-negative breast cancer (TNBC) cell line MDA-MB-231 and normal cell lines: human skin fibroblasts (CCD-25Sk) and human bronchial epithelium (BEAS-2B). The five compounds, 4a, 5a, 6a, 7a and 9a, exhibited a significant reduction in the cell viability of human BC cell lines. Analog 6a, which demonstrated high cytotoxic activity against MCF-7 and MDA-MB-231 cell lines with IC50 values of 14.00 µM and 5.83 µM, respectively, was also antitumorigenic in all biochemical assays. It increased p53 and Bax levels in MDA-MB-231 cells as well as significantly decreased Akt kinase levels in the tested cells, and effectively inhibited collagen biosynthesis. Finally, for the selected compounds, we computationally predicted their ADME properties and performed molecular docking to Akt protein kinase. The results of computational docking indicated that the preferred binding mode for all of them was the inactive form of Akt kinase, as in the case with known Akt allosteric inhibitors.

Resistance to therapy remains a significant challenge in cancer treatment, often due to the presence of a stem-like cell population that drives tumor recurrence post-treatment. Moreover, many anticancer therapies induce plasticity, converting initially drug-sensitive cells to a more resistant state, e.g. through epigenetic processes and de-differentiation programs. Understanding the balance between therapeutic anti-tumor effects and induced resistance is critical for identifying treatment strategies. In this study, we present a robust statistical framework leveraging multi-type branching process models to characterize the evolutionary dynamics of tumor cell populations. This approach enables the detection and quantification of therapy-induced resistance using high-throughput drug screening data involving total cell counts, without requiring information on subpopulation counts. The framework is validated using both simulated (in silico) and recent experimental (in vitro) datasets, demonstrating its ability to generate meaningful predictions.

Sphingosine kinase 1/2 (SphK1/2) promote the initiation and advancement of breast cancers. We performed screening on a compound library of SphK inhibitors using computer molecular docking and selected the most representative compound, ZFP-B34, for testing its antitumor activity in triple-negative breast cancer (TNBC). In TNBC cell lines ZFP-B34 effectively inhibits SphK1/2 activity, induces ceramide accumulation, and results in Sphingosine 1 phosphate (S1P) depletion without altering SphK1/2 expression in TNBC cells, making it a promising novel dual inhibitor of SphK1/2. ZFP-B34 effectively inhibits cell proliferation, cell cycle progression, and migration, leading to cellular growth arrest. ZFP-B34 induces reactive oxygen species (ROS) production and mitochondrial depolarization, leading to mitochondrial dysfunction. Simultaneously, it damages DNA, ultimately resulting in apoptosis. ZFP-B34 can also inhibit the activation of Akt-mammalian target of rapamycin (mTOR) while inducing c-Jun N-terminal kinase (JNK) activation in TNBC cells. In vivo, daily intraperitoneal injection of a single dose of ZFP-B34 effectively inhibits the growth of 4T1 allografts in mice. In conclusion, ZFP-B34 is capable of inhibiting SphK1/2 and delaying the growth of TNBC cells both in vitro and in vivo.

Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease primarily affecting women, manifested as cystic lung destruction, angiomyolipomas (AMLs) and lymphagioleiomyomas. The hallmark of LAM is the presence of abnormal perivascular epithelioid cells, referred to as LAM cells. LAM is classified into tuberous sclerosis-associated (TSC) and sporadic forms according to the presence or absence of TSC gene mutations. In recent decades, the benefit of mechanistic target of rapamycin (mTOR) inhibitors has been demonstrated in stabilising respiratory function, reducing AMLs, lymphangioleiomyoma and chylous effusions, and controlling TSC-associated seizures. In addition to mTOR inhibition, clinical trials have explored therapies targeting autophagy, receptors of tyrosine kinases (RTKs), nonreceptor tyrosine kinases (non-RTKs) and hormones. More recently, new treatments avenues involving immune microenvironment, histamine signalling and Src kinase inhibition have entered pre-clinical and/or clinical evaluation. This review summarises the multiple pathophysiological mechanisms in LAM and highlights the therapeutic targets identified to date. Several clinical trials have been described, offering insights into their potential application and further research.

In this project, a new platinum complex with the formula [Pt(DACH)(tert-pentylgly)]NO3, where DACH is 1R,2R-diaminocyclohexane and tert-pentylgly is 1,1-dimethylpropylglycine, was prepared and characterized using conductivity measurements, elemental analysis, LC mass, HPLC, and various spectroscopic methods. The CT-DNA binding with this compound was explored through absorption and emission spectroscopy. UV-Vis absorption studies revealed a hyperchromic effect in the spectra of DNA, indicating interaction. Furthermore, a competitive fluorescence spectroscopy using ethidium bromide showed that the complex binds to DNA via a groove binding mode. Circular dichroism (CD) spectroscopy demonstrated that the platinum complex can alter the secondary structure of DNA. Cytotoxicity studies were carried out on MCF7 and HCT116 cell lines, representing human breast and colorectal carcinoma, respectively. Molecular docking suggested that the Pt complex binds to DNA more strongly than oxaliplatin, predominantly through groove binding, which aligns with the experimental findings. In the molecular dynamics analysis, the fluctuations in RMSD for the DNA-complex and the RMSF assessment of DNA residues suggest that the DNA structure is unstable. The interaction of DNA with Pt compound leads to an increase in the radius of gyration and helical bending, which correlates with heightened flexibility and residual deviations.

Early discontinuation of adjuvant endocrine therapy (AET) among patients with estrogen receptor-positive (ER+) breast cancer (BC) is common. Observational studies reported inconsistent effects of early AET discontinuation on survival outcomes, with limited causal evidence.

Cisplatin is a widely used chemotherapeutic agent; however, its clinical utility is limited due to several organ toxicities, including nephrotoxicity, which is primarily mediated through oxidative stress, inflammation, and apoptosis. This study examines the protective effect of methyl jasmonate (MeJA) in mitigating cisplatin-induced nephrotoxicity by modulating the caspase-3/COX-2/NF-κB signaling pathway. Initially, we performed molecular docking to evaluate the binding affinity of MeJA against the caspase-3, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) proteins in the presence of the reference drug amifostine. Further, in vitro cell cytotoxicity on Madin-Darby canine kidney (MDCK) cells via MTT assay, oxidative stress, and proinflammatory markers. We have also performed an in vivo analysis of MeJA on cisplatin-induced nephrotoxicity in experimental rats by employing several biochemical parameters and histopathological investigation on rat kidney tissues. In silico molecular docking analysis revealed strong binding interactions between MeJA, key apoptotic and inflammatory mediators, suggesting its potential to regulate cisplatin-induced toxicity. In vitro studies using MDCK cells demonstrated that MeJA significantly reduced cisplatin-induced cytotoxicity, oxidative stress, and proinflammatory markers. In vivo experiments in rats further confirmed the nephroprotective effects of MeJA, as evidenced by improved renal function markers, and histopathological preservation of renal tubules and glomerulus tissues of rat kidneys. While ELISA testing revealed that MeJA downregulates caspase-3 and COX-2 expression and suppresses NF-κB activation. These findings collectively highlight the therapeutic potential of MeJA in alleviating cisplatin-induced nephrotoxicity through modulation of apoptosis and inflammatory pathways. MeJA may serve as a promising nephroprotective agent, warranting further clinical investigation for its potential application in oncology settings.

Cytochrome CYP1B1 is a member of the monooxygenase subfamily. It can lead to tumorigenesis by catalyzing the activation of a variety of exogenous carcinogens and endogenous estrogens. In addition, overexpression of CYP1B1 in hormone-related tumors can inactivate certain anticancer drugs, leading to resistance. Accordingly, selective inhibition of CYP1B1 expression represents a potential therapeutic strategy to overcome tumor drug resistance. To this end, we designed and synthesized 46 trans-styrylquinazolinone CYP1B1 inhibitors, The most important feature of these compounds is that the introduction of double bonds makes the molecular structure in the same plane to form a conjugated system. 7-Ethoxyresorufin-O-deethylase (EROD) screening revealed that one of these compounds exhibited an IC50 value of 6.75 × 10-3 nM against CYP1B1. Based on this initial hit, a series of 2-styrylquinazolin-4-amines were synthesized as a means to optimize inhibitory ability and water solubility. Aromatization and the introduction of amino groups was found to greatly improve inhibitory ability, with one such derivative presenting IC50 = 6.05 × 10-6 nM. Molecular docking experiments were used to explore the binding of the most potent compounds to CYP1B1. A549 cell experiments showed that three of the compounds (including the initial trans-styrylquinazolinone hit) significantly reversed resistance to paclitaxel and greatly inhibited invasion and migration, demonstrating the application potential of trans-styrylquinazolinone CYP1B1 inhibitors in the prevention and treatment of hormone-related tumors.

Immune checkpoint inhibitors (ICIs) have changed cancer treatment, evoking durable responses in various cancers. However, their immune-mediated mechanisms can lead to unique toxicities known as immune-related adverse events (irAEs), among which ICI-related pneumonitis (ICI-P) is a critical concern owing to its potential severity and impact on treatment continuity. This review provides a comprehensive overview of ICI-P, covering its epidemiology, pathophysiology, clinical features, diagnosis, risk factors, and treatments. ICI-P is more frequently observed in real-world settings than in clinical trials, especially in patients with risk factors such as pre-existing interstitial lung disease. The pathogenesis of ICI-P involves Th1/Th17 inflammation and autoantibody production, but the exact mechanisms remain unclear. An organizing pneumonia-like pattern is a characteristic radiological finding on chest computed tomography. Diagnosis can be supported by the evaluation of biomarkers like Krebs von den Lungen-6 and surfactant protein-D. High-dose corticosteroids are the standard treatment, although optimal regimens remain under investigation. Relapse is not uncommon, particularly in cases with an organizing pneumonia-like pattern or prolonged exposure to ICIs. Resuming ICIs after ICI-P is associated with a marked risk of relapse and must be carefully considered. Notably, immune modulation by ICIs may persist after discontinuation, potentially increasing susceptibility to drug-induced pneumonitis from subsequent therapies. As the use of ICIs expands, enhanced recognition, timely intervention, and individualized management of ICI-P are essential. Future strategies incorporating biomarkers, real-world data, and artificial intelligence may further improve outcomes for patients with ICI-P.

In a world where cancer continues to be a major health problem, the urgency continues to find new effective treatments. This work involved the synthesis of more than 10 anticancer fluoroquinolones (FQs) and pyridoquinoxaline (PQ) derivatives originating from FQs and studied their cytotoxicity, anti-adhesion, anti-invasion, and pro-apoptotic properties. Synthesis of the new compounds of the PQ series was carried out by reacting 1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid with L-proline, 3 and 4-hydroxy proline derivatives (compounds 2a-2f), followed by reductive cyclization to yield compounds 3a-3f. Compounds 2a and 3a gave favorable activities on MCF-7 with respective IC50 values of 5.9 and 0.9 μM, respectively, while the hydroxy derivatives almost lost activity on all tested cells. Due to the fact that the activity of PQs and precursor FQs was correlated to increased lipophilicity, the lipophilic FQs series 10a, 10b, 11a, and 11b were prepared by direct reaction of 1-cyclohexyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate with chloro or fluoro aniline, followed by ester hydrolysis 10a and 10b and reduction to yield the amine compounds 11a and 11b. All FQs 10a, 10b, 11a, and 11b showed very excellent cytotoxicity against all tested cell lines (mammary MCF-7, MDA-MB-231, and invasive prostate DU-145) with IC50 values below 20 μM with impressively favorable lack of any cytotoxicity in normal ligament PDL fibroblasts (in 3.125-200 μM). Only FQs exerted comparable or superior anti-adhesion and anti-invasion activity versus the antineoplastic reference quercetin. Significant incremental increases in the pro-apoptogenesis Bax/anti-apoptosis Bcl ratio revealed a physiologically regulated cytotoxicity via DNA fragmentation harvested in cytolysates. The structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) reveal that planarity due to a fused polycyclic system and lipophilicity were essential requirements for anticancer PQs, whereas a high number of hydrogen bonds (HBs) and increased number of chelators, in addition to lipophilic balance, are the major requirements for anticancer FQs. In vitro cell viability assays revealed pronounced affinity for reductions in cell viabilities for the targeted PQ-bearing AuNPs versus PQsalone (induced) incubations and basal (non-induced) controls after 48 h incubation with HT29 cells. These results are very promising upon optimization of the system.

Despite achieving complete remission (CR) through surgery, chemoradiotherapy, targeted therapy, and other treatment modalities, breast cancer, particularly triple-negative breast cancer (TNBC) remains at a high risk of recurrence and metastasis. Enhancing anti-tumor immunity to eliminate residual tumor cells may reduce TNBC relapse. Our previous research indicated low-intensity pulsed ultrasound (LIPUS) can activate the anti‑tumor immunity. Here, we explore the potential of the suitable strategy with LIPUS, and the combination with an immune checkpoint inhibitor, anti-PD-1 antibody (αPD-1) to anti‑tumor immunity in TNBC.

Targeted protein stabilization has emerged as a promising therapeutic strategy to combat various human diseases linked to aberrant protein degradation. However, the deubiquitinase-targeting chimera (DUBTAC) technology is still in its infancy, with only a few proteins being successfully stabilized. To this end, the stabilization of tumor suppressor proteins represents a critical therapeutic strategy to combat cancer, as their loss-of-function mutations and reduced expression are frequently implicated in the pathogenesis of diverse types of human cancer. In this study, we present an innovative PRO-DUBTAC platform that, for the first time, stabilizes tumor-suppressive E3 ubiquitin ligases as a novel anticancer therapeutic approach. Through the conjugation of E3 ligase ligands with a small-molecule ligand of the deubiquitinase OTUB1 via a linker, we developed two series of PRO-DUBTACs─VHL-DUBTAC and KEAP1-DUBTAC─that effectively stabilize the tumor-suppressive E3 ligases VHL and KEAP1 in cells, respectively, in an OTUB1-dependent manner to retard tumor cell growth. PRO-DUBTAC could be a versatile and generalizable platform for the selective stabilization of tumor-suppressor E3 ligases, thereby opening new therapeutic avenues for targeted cancer therapies by harnessing the tumor-suppressive potential of E3 ligases.

Colorectal cancer (CRC) continues to be a major global health challenge due to its high incidence and mortality rates, emphasizing the critical need for innovative therapeutic strategies. IL-1R2, a member of the IL-1 receptor family, plays a pivotal role in both tumorigenesis and antitumor immunity. However, its precise role in tumor development and its impact on immune checkpoint inhibitors (ICIs) therapy in CRC remain poorly understood. We examined tumor progression in wild-type and IL-1R2-deficient mice using an AOM/DSS-induced colitis-associated colorectal cancer model treated with combined ICIs therapy. Our findings revealed that IL-1R2 deficient mice exhibited a significant reduction in tumor burden, accompanied by alterations in the carcinogenic program and enhanced immunogenicity of tumor cells. Furthermore, the deletion of IL-1R2 resulted in an increased proportion of exhausted CD8+ T cells, a population commonly enriched for tumor antigen-specific T cells, suggesting an augmentation of tumor-specific immune responses. Moreover, IL-1R2 deletion upregulated genes linked to antigen presentation in dendritic cells, indicating enhanced activation of the adaptive immune system. Collectively, these findings position IL-1R2 as a promising therapeutic target for improving the efficacy of treatment strategies in CRC.

The genesis of head and neck cancer (HNC) is attributed to the combined influence of genetic and epigenetic irregularities. While surgical resection and radiotherapy remain primary treatment modalities, the effectiveness of current chemotherapeutic options is often hindered by toxicity, resistance, and limited selectivity. Hydroxyurea has long been recognized for its anticancer potential; however, its clinical application is limited by a short half-life, dose-dependent toxicity, and resistance mechanisms. To address these limitations, researchers have focused on developing novel hydroxyurea derivatives with improved pharmacokinetics, target specificity, and multimodal mechanisms of action. In the present study, we report the design and synthesis of two novel 2,2'-bipyridine hydroxamic acid derivatives, including a hydroxyurea analogue aimed at enhancing chemotherapeutic efficacy and safety. Compound 1A demonstrated selective cytotoxicity against Cal27 cells (IC50 = 19.36 μM). Mechanistic investigations revealed that 1A inhibits cancer cell migration and induces ROS-mediated apoptosis. Additionally, 1A exhibited moderate HDAC inhibition, supported by molecular docking and dynamics simulations, which confirmed stable binding to HDAC 2 isoform through Zn2⁺ coordination. These findings place compound 1A as a promising lead candidate, integrating epigenetic modulation and direct cytotoxic effects for potential therapeutic application in HNC.

Microsatellite instability (MSI) is a key feature of cancers with defective DNA mismatch repair, including colorectal, gastric, endometrial, and ovarian cancers. Tumors with MSI depend on the Werner syndrome protein (WRN) for genomic stability, making WRN an attractive therapeutic target. WRN inhibitors exploit the concept of synthetic lethality, inducing selective DNA damage and cell death in MSI tumors while sparing microsatellite stability (MSS) tumor cells or normal cells. Preclinical studies have shown that the efficacy of WRN inhibitors is enhanced when combined with DNA damage response inhibitors or immunotherapy. This review delineates the molecular mechanisms underlying WRN dependency in MSI cancers and explores the therapeutic potential of WRN inhibition. WRN inhibitors represent a promising strategy in precision oncology, especially for MSI tumors, and have the potential to enhance patient outcomes, either as monotherapy or in combination with other treatments.

Primary effusion lymphoma (PEL), which is caused by Kaposi sarcoma herpesvirus (KSHV), and Burkitt lymphoma (BL), a subset of which are associated with Epstein-Barr virus (EBV), are aggressive non-Hodgkin's lymphomas. Both have relatively poor survival compared to other lymphomas. Cereblon-binding immunomodulators (CBIs), such as pomalidomide (Pom), show in vitro efficacy and clinical activity against certain of these lymphomas. Next generation CBIs, such as golcadomide (Golc) and iberdomide (Iber), have increased affinity to the primary cellular target, cereblon, making them potentially better anticancer agents. Here, we report the in vitro activity of these novel CBIs against PEL and BL cell lines. Both Golc and Iber, but primarily Golc, caused substantial growth suppression of PEL and BL lines with much lower half-maximal inhibitory concentration (IC50) compared to Pom. This growth suppression was mediated, in part, by enhanced downregulation of interferon regulatory factor 4 (IRF4) in PEL cell lines. Additionally, both Golc and Iber increased immune surface markers such as ICAM-1, B7-2, and MHC-I in PEL and BL cells at lower concentrations than Pom; these increases led to enhanced recognition of both PEL and BL cells by T-cells. The novel CBIs had relatively little activity in Pom-resistant cell lines with low levels of cereblon, suggesting that binding to cereblon is also important for the functions of the novel CBIs. These data show that the newer CBIs are more potent and effective against PEL and BL lines than Pom, and therefore, are worth investigating clinically in patients with these tumors.