Drug resistance in cancer remains a major barrier to durable therapeutic benefits and limits the effectiveness of chemotherapy, targeted therapy, and combination treatment in multiple malignancies. Increasing evidence indicates that specific kinesin superfamily proteins contribute to tumor adaptation and therapeutic response in a context-dependent manner through their roles in mitotic regulation, intracellular transport, and stress-response pathways. Aberrant expression of multiple kinesin family members has been documented across diverse cancers and is frequently associated with aggressive clinicopathological features, poor prognosis, and resistance to treatment. However, expression alterations alone do not establish functional dependency, and mechanistic validation is required to distinguish true resistance drivers from adaptive tumor states. In this review, we summarize the classification, biological functions, and abnormal expression patterns of kinesins in cancer; discuss the major mechanisms through which they contribute to drug resistance; and examine strategies for targeting kinesins, including natural-product-derived direct inhibitors, small-molecule inhibitor development, rational combination approaches, and structure-guided and computational optimization strategies. We also evaluate the biomarker potential of kinesin dysregulation and the value of advanced preclinical models for mechanistic and translational investigations. Finally, we highlight the major challenges that hinder clinical translation, including target specificity, compensatory resistance, insufficient biomarker validation, and tumor heterogeneity. Future progress will require integration of functional genomics, multiomics profiling, and mechanism-guided therapeutic strategies to determine when kinesin inhibition represents a clinically actionable approach for resistant malignancies.
Hypoxia‐inducible factor‐1 α (HIF‐1α) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti‐tumor drugs. YC‐1 (1‐benzyl‐3‐(5’‐hydroxymethyl‐2’‐furyl)indazole), as a classic inhibitor of HIF‐1α, has received extensive attention in multiple anti‐tumor studies. Some derivatives that replace YC‐1 indazole with the benzimidazole skeleton have shown certain HIF‐1α inhibitory and anti‐tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF‐1α inhibitory and anti‐tumor effects were screened and investigated. In vitro anti‐proliferation and dual‐luciferase reports showed that compound 9o had superior in vitro anti‐tumor (IC50 = 33.85 μM) and HIF‐1α transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC‐1. Meanwhile, compound 9o can also significantly inhibit the colony formation and survival rate of HCT‐116 cells. In addition, Western blotting, real‐time PCR and and lactic acid content experiments verified its inhibitory effect on HIF‐1α and downstream glycolysis. In addition, compound 9o was found to reduce platelet aggregation more than YC‐1, and the molecular docking results suggested that compound 9o weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound 9o can inhibit tumor growth and reduce the levels of HIF‐1α and glycolysis rate‐limiting enzyme HK2 in HCT‐116 tumor‐bearing mice. The acute toxicity results also demonstrated the safety of compound 9o in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti‐tumor candidate compounds based on HIF‐1α inhibitors.
Qixian Yang, Jing Zhang, Meijing Liu et al.· Drug development research (P...· 0 citations
Results highlight lncRNA ABCA9-AS1 as a novel and promising prognostic biomarker that promotes gastric cancer progression by acting as a ceRNA to modulate the miR-497-5p/KIF23 axis.
Yiwen Wu, Yiniu Xia, Hanyu Liu et al.· Current Cancer Drug Targets· 0 citations
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