Anti-Cancer Agents in Medicinal Chemistry - Online First

Cyclooxygenase, an enzyme that occurs in at least two distinct variants (COX-1 and COX-2), is the target of classical inhibitors, which lack selectivity and inhibit both types of COX. However, a recent approach focuses explicitly on inhibiting COX-2, commonly found in inflamed tissue, resulting in fewer adverse effects than COX-1 inhibitors.

A series of 4-(4-(methylsulfonyl)phenyl)-6-phenylpyrimidin-2-amine derivatives were synthesized through a two-step process. First, 4-substituted acetophenones underwent base-catalyzed Claisen-Schmidt condensation with 4-(methylsulfonyl)benzaldehyde to yield chalcones, which were then cyclized with guanidine hydrochloride under basic reflux conditions. Molecular docking was performed using AutoDock Vina software. The inhibitory activities of COX-1 and COX-2 were evaluated using enzymatic assays. Antiplatelet aggregation was measured via a turbidimetric method, and antiproliferative activity was assessed using the MTT assay.

The in vitro experiments on COX inhibition revealed that a substantial number of the synthesized compounds presented a strong suppressive effect against COX-2. The assessment of antiplatelet aggregation activity indicated that most of the derivatives effectively inhibited ADP-induced platelet aggregation. Compound 4i exhibited the most potent antiproliferative activity, comparable to cisplatin. The docking studies and molecular modeling results demonstrated that the designed compounds, except for 4b, exhibited a binding behavior comparable to that of celecoxib. In addition, the insertion of the SO2Me moiety within the secondary binding site of COX-2 was observed.

These findings suggest that the structural modifications introduced in the synthesized derivatives contribute significantly to their selective COX-2 inhibition and antiplatelet properties. The correlation between docking results and biological assays supports the rationale behind the design of the compound.

The 4-(4-(methylsulfonyl)phenyl)-6-phenylpyrimidin-2-amine exhibits unique properties as a COX-2 inhibitor, displaying effective inhibition of COX-2 while showing minimal interaction with the COX-1 enzyme. Furthermore, our study revealed that most of these compounds exhibited inhibitory effects on ADP-induced platelet aggregation.

Melanoma, an aggressive skin cancer, has seen treatment advancements with immune checkpoint inhibitors (ICIs) like ipilimumab and nivolumab. Despite improved survival rates, resistance remains a challenge. The recent focus on lymphocyte activation gene-3 (LAG-3) inhibitors, such as relatlimab, shows promise in combination therapies, potentially improving outcomes with fewer adverse effects. This review evaluates the safety and efficacy of anti-LAG-3 antibodies in melanoma treatment.

This systematic review and meta-analysis, following the PRISMA guidelines and registered in PROSPERO (CRD42024565756), assessed anti-LAG-3 antibodies in melanoma treatment. A thorough search across PubMed, Embase, Scopus, and Web of Science up to January 2024 yielded relevant studies. Data on study characteristics, patient demographics, disease characteristics, treatment details, and clinical outcomes were extracted. Quality assessment was performed using the MINOR criteria. The meta-analysis, using STATA and random-effects models, addressed heterogeneity to determine safety and efficacy outcomes.

We examined the clinical benefit of this combination therapeutic approach by measuring several primary endpoints and running a meta-analysis to determine the pooled estimate of 6-month progression-free survival (PFS), 1-year PFS, 6-month duration of response (DoR), 1-year DoR, 1-year overall survival (OS), 2-year OS, partial response (PR), complete response (CR), objective response rate (ORR), disease control rate (DCR), stable disease (SD), and progressive disease (PD) for patients diagnosed with melanoma. Our analysis showed 66% of any grade treatment-related adverse events (trAEs) (95% CI: 51%-81%), 19% of grade ≥ 3 trAEs (95% CI: 11%-27%), 12% of any grade AEs leading to discontinuation (95% CI: 9%-14%), and 8% of grade ≥ 3 AEs leading to discontinuation (95% CI: 6%-10%). 76% of any grade overall AEs (95% CI: 34%-100%), and 33% of grade ≥ 3 overall AEs (95% CI: 15%-50%). The most common AEs were fatigue, pneumonitis, rash, pruritus, colitis, hepatitis, diarrhea, hypothyroidism, thyroiditis, and adrenal insufficiency.

This systematic review and meta-analysis provide comprehensive evidence regarding the safety and efficacy of anti-LAG-3 antibodies in melanoma therapy. Pooled data reveals encouraging outcomes across several key endpoints, including PFS, OS, and ORR. While trAEs were common (66% for any grade and 19% for grade ≥3), most were manageable.

Anti-LAG-3 therapy is an active and safe treatment that shows promising results in melanoma treatment.

The smooth muscle α-actin 2-antisense 1 (ACTA2-AS1), also known as ZXF1, is an emerging cancer-associated long non-coding RNA (lncRNA) that has garnered significant attention in recent years. ACTA2-AS1 is situated on human chromosome 10 at location 10q23.31, comprising five exons and a single transcript. The aberrant expression of ACTA2-AS1 has been noted in 10 malignant tumors, correlating significantly with unfavorable clinicopathological characteristics and poor patient prognosis.

This review encapsulates recent progress in ACTA2-AS1 research, examining its expression profile, biological functions, molecular mechanisms, and anticipated influence on cancer diagnosis, treatment, and prognosis, emphasizing its potential as a novel therapeutic target based on lncRNA and its prognostic utility as a biomarker.

Based on a comprehensive search of the PubMed database for the biological function of lncRNA ACTA2-AS1 in malignant tumors, the current research is systematically summarized and critically analyzed.

ACTA2-AS1 plays a complex role in various biological processes in tumor cells, encompassing proliferation, apoptosis, and cell cycle arrest. It also contributes to migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. Mechanistically, ACTA2-AS1 influences oncogenic or tumor-suppressive effects via a complex regulatory network. It can adsorb specific 5 miRNAs as competitive endogenous RNAs (ceRNAs), thereby mitigating the suppression of downstream mRNA targets implicated in tumorigenesis (e.g., SOX7, KLF9, CXCL2, BCL2L11, etc.) and modulating their downstream signaling pathways (e.g., Wnt5a/PKC, SMAD3, mTOR, etc.), demonstrating a broad spectrum of dual roles in carcinogenesis and tumor suppression.

ACTA2-AS1 is a promising biomarker and molecular target for the treatment of cancer.

PD-L1 plays a pivotal role as an immunoregulatory checkpoint within the immune system, exerting a critical influence on the internal functioning and survival mechanisms of cancer cells. Our study aimed to elucidate the clinical significance of PD-L1 expression in circulating tumor cells (CTCs) derived from individuals afflicted with Hypopharyngeal and Laryngeal Cancers (HLC).

To verify the relationship between the expression of PD-L1 in CTCs in HLC and the consistency in tissue and the preliminary clinical application.

A laboratory-based experimental study was carried out at Fujian Medical University Union Hospital. CTCs were identified using an immunomagnetic positive sorting methodology. Simultaneous detection was conducted on the CTC levels among PD-L1 positive patients, aiming to ascertain the dynamic relationship between real-time CTC fluctuations and the clinicopathological indices of the patients. This investigation encompassed a cohort of 38 individuals, wherein PD-L1 expression analysis was executed to delineate CTC variations in PD-L1-positive patients.

The constructed immunolipid magnetic nano-beads demonstrated pronounced efficacy in capturing CTCs, and the lipid nanoparticles exhibited noteworthy capture efficiency coupled with minimal cytotoxic effects. The assessment of PD-L1 expression consistency between CTCs and tissue specimens revealed a substantial agreement surpassing 70%. Furthermore, inhibition of PD-L1 yielded a significant elevation in the cytokine TNF-α levels, accompanied by a concomitant reduction in IL-10 levels.

The CTC sorting system devised in this investigation boasts attributes of remarkable specificity and sensitivity. By virtue of PD-L1 expression analysis, it holds the potential to offer instructive implications for tailoring individualized treatments in clinical scenarios.

Breast cancer is an abnormal cell growth that develops in the breast and spreads throughout the body. Despite cancer being the second leading cause of death, survival rates are increasing as a result of progress in cancer screening and therapy. Breast cancer is the most frequently diagnosed cancer type among women, but in most cases, there are no obvious symptoms. Screening mammograms can be used for early detection of cancer. The size of the tumor and the extent of cancer spread determine the type of needed treatment. There are different forms of treatment, where targeted therapy is generally the least harmful. It targets specific characteristics of cancer cells, such as human epidermal growth factor receptor 2 (HER2). Tyrosine kinase inhibitors are effective targeted treatment of HER2 positive breast cancer. A newer class has emerged, cyclin dependent kinase (CDK4/6), which is used to treat metastatic breast cancer.

Although CDK4/6 inhibitors class of therapy has revolutionized the treatment of metastatic breast cancer, some patients showed resistance and decreased efficacy. This study is the first to propose innovative computational strategies to improve the effectiveness and pharmacokinetic properties of existing HER2/CDK4/6 inhibitors anti-cancer agents. Through computer-aided drug design, the activity of existing breast cancer drug candidates has been tested. Structural modifications have been applied for in-silico optimization of their biological activity.

In this research, twenty-two analogues of the tested compounds have been proposed. Their biological activity and pharmacokinetic properties (ADMET) have been tested using BIOVIA Discovery Studio software.

Out of the designed analogous compounds, seven proposed structures demonstrated superior efficacy compared to the original drugs. The research study docking studies revealed that modifications to lapatinib and tucatinib improved binding affinity to HER2 by 15-25%, with docking scores of -18.34 kcal/mol and -1.04 kcal/mol, respectively. Similarly, CDK4/6 inhibitors exhibited enhanced selectivity, with abemaciclib showing the highest binding energy of -13.2 kcal/mol. ADMET predictions suggested improved solubility and reduced toxicity risks compared to the original drugs.

The research study results demonstrate that the synthesis of more lipophilic analogues of lapatinib or tucatinib and, likewise designing of fluorinated derivatives of CDK4/6 inhibitors play a crucial role in improving the efficacy of these anti-cancer agents. These findings highlight the potential of the proposed modifications as promising candidates for further pharmacological and in vitro and in vivo clinical validation.