Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure−activity relationships, and future directions of dual-target tubulin inhibitors.

Autophagy-based protein degradation is emerging as a promising technology for anti-diseases and innovative drug discovery.

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Physical exercise is of great significance for maintaining human health. Exercise can provide varying degrees of benefits to cognitive function at all stages of life cycle. Currently, with the aging of the world’s population and increase of life expectancy, cognitive dysfunction has gradually become a disease of high incidence, which is accompanied by neurodegenerative diseases in elderly individuals. Patients often exhibit memory loss, aphasia and weakening of orientation once diagnosed, and are unable to have a normal life. Cognitive dysfunction largely affects the physical and mental health, reduces the quality of life, and causes a great economic burden to the society. At present, most of the interventions are aimed to maintain the current cognitive level and delay deterioration of cognition. In contrast, exercise as a nonpharmacological therapy has great advantages in its nontoxicity, low cost and universal application. The molecular mechanisms underlying the effect of exercise on cognition are complex, and studies have been extensively centered on neural plasticity, the direct target of exercise in the brain. In addition, mitochondrial stability and energy metabolism are essential for brain status. Meanwhile, the organ-brain axis responds to exercise and induces release of cytokines related to cognition. In this review, we summarize the latest evidence on the molecular mechanisms underlying the effects of exercise on cognition, and point out directions for future research.

c-Jun N-terminal kinases (JNKs), members of the mitogen-activated protein kinase (MAPK) family, are encoded by three genes: jnk1, jnk2, and jnk3. JNKs are involved in the pathogenesis and development of many diseases, such as neurodegenerative diseases, inflammation, and cancers. Therefore, JNKs have become important therapeutic targets. Many JNK inhibitors have been discovered, and some have been introduced into clinical trials. However, the study of isoform-selective JNK inhibitors is still a challenging task. To further develop novel JNK inhibitors with clinical value, a comprehensive understanding of JNKs and their corresponding inhibitors is required. In this Perspective, we introduced the JNK signaling pathways and reviewed different chemical types of JNK inhibitors, focusing on their structure–activity relationships and biological activities. The challenges and strategies for the development of JNK inhibitors are also discussed. It is hoped that this Perspective will provide valuable references for the development of novel selective JNK inhibitors.