Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Online First

Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine protein kinase involved in regulating key cellular processes, including cell cycle progression, apoptosis, embryonic development, spliceosome assembly, and gene expression. Notably, MELK is overexpressed in Triple-Negative Breast Cancer (TNBC), an aggressive malignancy associated with poor prognosis, high drug resistance, and limited treatment options. Given its critical role in TNBC pathogenesis, MELK has emerged as a potential biomarker and therapeutic target. This review explores the molecular functions of MELK, its involvement in oncogenic signaling pathways, and the development of MELK-targeting small-molecule inhibitors.

A comprehensive literature review was conducted to evaluate current knowledge on MELK, including its molecular functions, interactions within signaling pathways, role in TNBC progression, and potential as a therapeutic target. Relevant databases, including PubMed, Web of Science, Embase, and Scopus, were searched for studies related to MELK expression, signaling mechanisms, and experimental therapeutic approaches.

MELK plays a central role in oncogenic signaling pathways that drive TNBC proliferation and survival. Preclinical studies have demonstrated that MELK inhibition can suppress TNBC cell growth and enhance chemotherapy efficacy. Several small-molecule inhibitors targeting MELK have shown promising anti-tumor activity in preclinical models. However, challenges remain in translating these findings into clinical applications due to drug specificity limitations and resistance mechanisms.

MELK is a promising biomarker and therapeutic target in TNBC. However, further research is required to refine MELK inhibitors, enhance clinical efficacy, and overcome drug resistance mechanisms. Targeting MELK could offer a novel therapeutic strategy to improve TNBC treatment outcomes.

This study explores the therapeutic potential of Nigella sativa L. and its key bioactive compound, thymoquinone (TQ).

Pancreatic cancer presents a significant health challenge due to its aggressiveness and limited treatment options. N. sativa and its component TQ have demonstrated anticancer properties in other cancers, warranting exploration in pancreatic cancer models.

To assess the antiproliferative, apoptotic, and anti-invasive effects of N. sativa extracts and TQ on pancreatic cancer cells, with a focus on modulating the NRF2/HO-1 and TNF-α signaling pathways.

MIA PaCa-2 and PANC-1 pancreatic cancer cell lines were treated with essential and fixed oils, methanol extracts (from Türkiye and Syria), and TQ. Cell viability, apoptosis, and invasiveness were assessed via XTT, Annexin V, and Matrigel assays, respectively. Gene expression and cytokine levels were evaluated using RT-qPCR and ELISA. HPLC was conducted to confirm TQ concentrations in extracts.

The methanol extract of Türkiye-originated N. sativa seeds (TM) exhibited the highest cytotoxic effect, reducing cell viability in MIA PaCa-2 and PANC-1 at 0.05 mg/mL, while TQ significantly decreased viability at 20 µM. TM reduced MIA PaCa-2 and PANC-1 invasiveness (42 ± 1.23 and 35 ± 0.73, respectively) and contained a higher concentration of TQ (7.9168 ± 0.0561%) compared to the Syria-originated extract (SM).

The findings suggest that TM and TQ exhibit strong anticancer potential by modulating key signaling pathways in pancreatic cancer cells, supporting their potential for further development as therapeutic agents in pancreatic cancer treatment.

Cancer is a global health burden. Despite advances in early detection and therapeutics, cancer prevalence continues to increase, underscoring the need for innovative therapeutic strategies. Dysregulation of cell death mechanisms is a hallmark of cancer that can lead to apoptosis evasion, which strongly contributes to tumor progression and therapy resistance. Isothiouronium salts have attracted attention as promising antitumor agents. This study aimed to evaluate the in vitro antitumor effect of an isothiouronium salt (IS-MF08) on the B16F10 melanoma cell line.

The antitumor properties of IS-MF08 were investigated by incubating B16F10 cells with the compound at different concentrations. Cytotoxicity was determined by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay, cell cycle arrest and cell death mechanisms by flow cytometry, and morphological alterations by transmission electron microscopy. Physicochemical parameters related to drug-likeness were predicted in silico using the SwissADME tool.

IS-MF08 was cytotoxic to melanoma cells, triggering cell cycle arrest and disrupting mitosis. The mechanism of cell death was compatible with apoptosis, as indicated by annexin V-FITC experiments and the relevant morphological changes in cell structure observed by transmission electron microscopy. SwissADME predicted that IS-MF08 has good physicochemical properties related to absorption and permeation.

The numerous mechanisms of cell death triggered by IS-MF08 and its drug-likeness make it an interesting molecule in the search for new antitumor compounds, contributing to therapies targeting the dysregulation of cellular mechanisms such as apoptosis.

GPR87 is an orphan G-protein-coupled receptor (GPCR) that represents a potential molecular target for developing novel drugs aimed at treating squamous cell carcinomas (SCCs) or adenocarcinomas of the lungs and bladder.

The present study aims to identify potential LPA analogues as inhibitors of the GPR87 protein through computational screening. To achieve this, the human GPR87 structure was modeled using template-based tools (Phyre2 and SWISS-MODEL), iterative threading (I-TASSER), and neural network-based de novo prediction (AlphaFold2). The modeled structures were then validated by assessing their quality against template structures using Verify-3D, ProSA, and ERRAT servers.

We conducted a comprehensive structural and functional analysis of the target protein using various computational tools. Several computational techniques were employed to explore the structural and functional characteristics of the target, with LPA selected as the initial pharmacological candidate. A library of 2,605 LPA analogues was screened against orphan GPR87 through in-silico docking analysis to identify higher-affinity and more selective potential drugs.

Molecular dynamics (MD) simulations were performed to track structural changes and convergence during the simulations. Key metrics, including the root mean square fluctuation (RMSF) of Cα-atoms, radius of gyration, and RMSD of backbone atoms, were calculated for both the apo-form and the LPA-GPR87 complex structures. These studies on structure-based drug targeting could pave the way for the development of specific inhibitors for the treatment of squamous cell carcinomas.

These findings may contribute to the design and development of new therapeutic compounds targeting GPR87 for the treatment of SCC.

Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting almost half of the population of the world. Some specific virulence genes of this bacterium have a significant causal effect on the outcome of gastrointestinal diseases. Therefore, the aim of this study was to evaluate the expressions of the cagA, dupA, sabA, babA, and iceA1 genes of H. pylori cultured from biopsy specimens of patients with GC and PUD and to compare these expressions with those in NUD patients as the control group.

The patients with gastrointestinal disorders referred to Shahid-Beheshti Hospital in Qom, Iran, were enrolled in this study. Eleven biopsies per patient were collected and used for culture, pathology, and rapid urease tests. Based on endoscopic and pathological findings, patients were separated into three groups: GC, PUD, and NUD. Colonies suspected of H. pylori were initially investigated using conventional evaluations and then confirmed by PCR assay. Also, the RT-qPCR method was used to evaluate the expression of target genes, including cagA, dupA, sabA, babA, and iceA1 in isolated strains.

One hundred and seventy-seven patients, including 31 GC, 55 PUD, and 91 NUD, were included in this study. Among the enrolled patients, 29 patients were positive for H. pylori based on three evaluation methods. The expression of bacterial cagA, dupA, and babA genes in the GC patients was statistically higher than in the NUD group. The expression of the sabA gene in the strain isolated from the GC group was lower than in the control group. No significant difference was observed between the GC group and the control group regarding the iceA1 gene.

Our finding shows that the expressions of cagA, dupA, and babA virulence genes in H. pylori strains isolated from gastric biopsies of both GC and PUD patients are significantly higher than the NUD ones. Therefore, screening and treating the infection caused by this bacterium and determining the genotype in patients may prevent the progression of the disease.

Certain types of non-Hodgkin lymphoma, such as Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL), often necessitate multiple treatment approaches. One promising avenue is immune checkpoint inhibition, specifically targeting the programmed cell death protein 1 (PD-1). Pembrolizumab, an immunotherapy medication, acts by inhibiting the PD-1 pathway and has gained approval from the United States Food and Drug Administration (FDA) for treating various cancers, including melanoma, Hodgkin lymphoma, lung cancer, and endometrial cancer. This meta-analysis aims to assess the impact of pembrolizumab on patient outcomes and survival in the context of B-cell lymphoma.

This study adhered to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Two independent reviewers conducted a thorough search of electronic databases up to September 28, 2023. We included studies that investigated the effects of pembrolizumab treatment on patient outcomes and survival in individuals diagnosed with B-cell lymphoma. All statistical analysis was performed by STATA V.17.

Our meta-analysis encompassed 13 eligible clinical trials involving 426 B-cell lymphoma patients. The study findings revealed a Disease Control Rate (DCR) of 63%, Overall Response Rate (ORR) of 42%, Complete Response Rate (CRR) of 23%, and 1-year Overall Survival Rate (OSR) of 64%. Notably, 65% of patients experienced Treatment-Related Adverse Events (TRAEs) of any grade, with 39% encountering grade ≥ 3 TRAEs. The most prevalent grade ≥ 3 TRAEs included anemia, neutropenia, thrombocytopenia, and lymphopenia.

The utilization of pembrolizumab, both as a monotherapy and in combination with other drugs, presented encouraging outcomes in patients with B-cell lymphoma.