Anti-Cancer Agents in Medicinal Chemistry - Volume 26, Issue 1, 2026

Cancer progression is increasingly understood to be influenced by neural mechanisms, including neurotransmitter signaling, neurotrophic factor activity, neuroinflammation, and neurogenic inflammation. These neurobiological interactions contribute to tumor proliferation, angiogenesis, and metastasis. Kinase inhibitors, a class of targeted therapies that block dysregulated kinase activity, have demonstrated promise not only in direct tumor suppression but also in modulating neural pathways associated with cancer progression.

This review examines the role of kinase inhibitors in modulating cancer-associated neural mechanisms. A comprehensive literature search was conducted to identify studies exploring the effects of kinase inhibition on: (1) neurotransmitter signaling pathways; (2) neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF); (3) neuroinflammation through glial cell modulation; and (4) neurogenic inflammation. Additionally, we assessed the impact of kinase inhibitors on tumor-induced axonogenesis and stress-related signaling. Clinical relevance was evaluated through analysis of preclinical models, human case studies, and outcomes from relevant clinical trials.

Kinase inhibitors were found to significantly modulate neural factors that facilitate tumor growth. Specifically, they can suppress neurotrophic signaling (e.g., NGF/TrkA, BDNF/TrkB), inhibit glial activation, reduce pro-inflammatory cytokine production, and block neurotransmitter-induced proliferation. Inhibition of stress-responsive kinases such as p38 MAPK and JNK also disrupted tumor-associated axonogenesis and inflammation. Clinical trials demonstrate improved outcomes in cancers such as glioblastoma, breast cancer, and pancreatic cancer when kinase inhibitors are employed with consideration of neural mechanisms.

These findings support the emerging concept of targeting the neural tumor microenvironment as a therapeutic strategy. Kinase inhibitors represent a dual-action approach, suppressing both cancer cell intrinsic growth pathways and the neural factors that sustain them. However, several challenges persist, including resistance mechanisms, variability in patient neural profiles, and off-target effects. Future research should focus on the development of neural-specific kinase inhibitors, the use of neural biomarkers for therapy selection, and the integration of neuro-oncology into personalized treatment plans.

Kinase inhibitors offer a promising frontier in cancer treatment by targeting neural mechanisms that contribute to tumor progression. While current evidence is encouraging, further investigation is required to optimize their use within neuro-oncology. Personalized approaches and novel targets within the neural-cancer axis will be essential for translating this strategy into clinical practice and improving long-term patient outcomes.

Herpes zoster (HZ) is a common complication in patients with malignant tumors (MT), impacting prognosis. Immunocompromised states due to malignancy or treatment increase HZ risk. However, comprehensive assessments of HZ's clinical features and its impact on prognosis in these patients are limited, general conclusions are challenging, prompting a systematic review and meta-analysis to better understand the relative risk of HZ in malignancy.

To assess the clinical features and prognostic factors of HZ in cancer patients through systematic review and meta-analysis. The study aimed to calculate the relative risk of HZ in malignancy and analyze factors affecting prognosis, such as age, gender, tumor type, and treatment.

A systematic search in PubMed (2016-2024) identified studies on HZ and malignancy. Two reviewers independently screened and selected studies, extracting data on study characteristics, population demographics, and outcomes. Statistical heterogeneity across the studies was addressed using random-effects models, while subgroup analyses were performed to identify potential sources of heterogeneity.

Out of the 633 records reviewed, 13 studies satisfied the eligibility criteria and were incorporated into the meta-analysis. The combined relative risk for any type of cancer was found to be 1.82(95% CI: 1.29,2.57). The combined relative risk for any solid tumors was 1.63(95% CI: 1.08,2.46). The combined relative risk for any haematological cancer was 3.43(95% CI: 1.33,8.86). The combined analysis of all treatment modalities (including Radiotherapy, Chemotherapy, Immunosuppression, HSCT) shows a significant overall effect with a risk ratio of 1.78(95%CI: 1.59,2.00).

Cancer patients have increased HZ risk due to immunosuppression from the malignancy and its treatment, especially in hematological cancers and those undergoing stem cell transplantation.

Aurone based compounds exhibited antioxidant and anti-inflammatory potential and documented for their anticancer potential. The anticancer potential of aurone derivatives AU3, AU4, AU5, AU7, and AU10 is yet to be studied against breast cancer.

The present work was undertaken to evaluate the anticancer potential of aurone based test compounds AU3, AU4, AU5, AU7, and AU10 in breast cancer cell lines MCF-7.

The azaindole based aurones were synthesized by the condensing 4,6-dimethoxybenzofuran-3(2H)-one derivative with various indole aldehydes in the presence of sodium hydroxide. The MCF-7 breast cancer cell line was used to assess the cytotoxic effects of these compounds. Molecular docking studies of the synthesized compounds against the Cyclin-dependent kinase 2 (CDK2)/Cyclin A complex were conducted.

Our experimental findings demonstrated that AU3, AU4, AU5, AU7, and AU10 elicited significant effects on MCF-7 by virtue of its minimum cell viability, with IC50 values of 70.14 µM, 87.85 µM, 133.21 µM, 52.79 µM, and 99.55 µM, respectively, thus, exhibits potential anticancer action. Further, to corroborate the anticancer potential, we investigated mechanisms of action through molecular docking studies with the CDK2/Cyclin A complex (PDB: 6GUC) and their findings demonstrated that test compounds showed robust binding through various interactions, including hydrogen bonds, Pi-interactions, and Alkyl bonds with key residues such as Lys129, Asp127, Gln131, and Asp145. Test compounds AU3 and AU7, exhibited better binding affinities and diverse interaction profiles, suggesting a potent disruption of CDK2/Cyclin A activity.

Thus, in conclusion, our findings revealed that AU3, AU4, AU5, AU7, and AU10 elicited anticancer action and their effects through CDK2/Cyclin A disruption.

To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer.

Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors.

In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo.

The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer. The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

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.

The presence of severe hypoxic stress can drive tumor growth, angiogenesis, and metastatic characteristics via up-regulated hypoxia-inducible factor 1-alpha (HIF-1α). Hence, targeting HIF-1α is considered a promising strategy, as increased HIF-1α activity is a key factor in the aggressive phenotype of malignancies. In this study, we aimed to investigate the anti-cancer effects of several flavonoids, both single and in combination with PX-478, in breast cancer cell lines.

We tested the effects of luteolin and PX-478, both alone and in combination, on HIF-1α level in breast cancer cells under hypoxia using the cell viability assay. To determine the rationale for the cell growth inhibition induced by the luteolin+PX-478 combination, we conducted experiments to assess cell survival, apoptosis, cell cycle, invasion, and migration under both normoxic and hypoxic conditions. Furthermore, we evaluated the effect of this combination on DNA damage response under hypoxic stress via Comet assay and immunofluorescence staining.

Our findings revealed that the luteolin+PX-478 combination significantly suppressed the growth of MDA-MB-231 cells. In addition, we assessed time-dependent expression of HIF1α in MDA-MB-231 cells and observed that the combination of luteolin and PX-478 down-regulated the HIF-1α level. Finally, we found that the luteolin+PX-478 combination induced apoptosis and G2 cell cycle arrest and enhanced DNA damage response. This combination also sensitized breast cancer cells to ionizing radiation in hypoxic stress.

The findings suggested that targeting HIF-1α with a combination of luteolin and PX-478 may provide a synergistic approach to suppressing tumor growth and enhancing therapeutic response under hypoxic conditions. The observed effects on apoptosis, cell cycle arrest, and DNA damage response indicated that this combination could be a promising strategy for overcoming hypoxia-induced resistance in breast cancer therapy.

Collectively, our results suggested the combination of luteolin and PX-478 to enhance the anti-cancer effects of PX-478 in breast carcinoma cells by impeding the cell growth and inducing DNA damage response under hypoxia.