Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Current Issue

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.

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.

This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7’-oxycoumarin)-[1,2,4]triazolo[1,5-a]pyrimidine scaffold.

The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells.

In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with KI values ranging from 0.75 to 10.5 μM, while hCA I, II, IV isoforms were not significantly inhibited (KIs > 100 μM). Compound 3d emerged as the most potent and selective inhibitor, with KIs of 0.92 and 0.75 μM for hCA IX and XII, respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines, particularly HD-MB03, when it was studied for its adjuvant effects in combination with cisplatin.

In this study, we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices > 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

This study aimed to explore the roles of BCL6 and STAT4 in breast cancer, their biological functions, and their relationships with the prognosis of patients with breast cancer.

Online databases were used to analyze the expression characteristics of BCL6 and STAT4 in breast cancer, as well as the correlation between STAT4 and both the prognosis of breast cancer patients and the biological function of breast cancer cells. BC cell lines, such as MCF7 and MDA-436 cells, were treated with the BCL6 inhibitor TP-021, and STAT4 and BCL6 mRNA expression levels were detected. Sh-RNAs were used to downregulate STAT4 in MCF7 and MDA-436 cells, and their proliferation ability was measured via a CCK-8 assay.

BCL6 expression was detected in BC cell lines and tissues, but the expression of STAT4 was downregulated in BC, and the expression level of STAT4 was negatively correlated with patient prognosis. Inhibition of BCL6 can increase the STAT4 level in BC cells and inhibit their proliferation ability in vitro. Poor prognosis may be related to the expression of STAT4 and the characteristics of immune cell infiltration in tumor tissues.

BCL6 inhibitors demonstrated therapeutic effects on breast cancer cells through the BCL6-STAT4 pathway.

The Src Homology 2 (SH2) domain, the most conserved region of STAT5a/b (aa 573–712), is crucial for receptor-specific recruitment and STAT5 dimerization, making it a therapeutic target in prostate cancer (PCa).

This study explored the SH2 domain of STAT5a and carried out the identification of natural STAT5a inhibitors.

Using template-based homology modeling, we constructed the structure of human STAT5a (VP1P) and compared it with its 3D crystal of the STAT5a protein obtained from the RCSB database and the model generated by the AlphaFold database. In this study, we carried out molecular docking studies using AutoDock Vina on the top 500 natural compounds identified through a pharmacophore search of the ZINC database using ZINCPharmer. Furthermore, the top ten compounds with the highest binding energies were evaluated for their drug-likeness and ADMET properties using SWISS ADME and ProTox-II, followed by 100 ns molecular dynamics (MD) simulations using the Desmond module of the Schrodinger suite.

Docking studies revealed Pedunculagin (-10.5 kcal/mol), Folic acid (-10.1 kcal/mol), Chebulinic acid (-10.0 kcal/mol), Chebulagic acid (-9.8 kcal/mol), and Oleandrin (-9.8 kcal/mol) as the top candidates, compared to the STAT5 inhibitor (Phase-II Clinical Trial) (-8.5 kcal/mol). ADMET analysis confirmed their safety profiles. MD simulations showed stable protein-ligand complexes, with all compounds interacting with the conserved Arg638 residue at the active site, similar to the STAT5 inhibitor.

Pedunculagin demonstrated the strongest binding energy and stability, making it a promising candidate for further development as a novel lead compound to disrupt STAT5a/b dimerization in PCa therapy.