Abstractp53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53–MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53–MDM2 interaction.

Individuals with PIU were more impulsive than controls and shared neuropsychological and ERPs characteristics of compulsive-impulsive spectrum disorder, which supports that PIU is an impulse disorder or at least related to impulse control disorder.

Individuals with IAD and PG patients present deficiencies in working memory, executive dysfunction and impulsivity, and individuals with IAD are more impulsive than PG patients.

BackgroundThe cue-related go/no-go switching task provides an experimental approach to study individual’s flexibility in changing situations. Because Internet addiction disorder (IAD) belongs to the compulsive-impulsive spectrum of disorders, it should present cognitive bias and executive functioning deficit characteristics of some of these types of disorders. Until now, no studies have been reported on cognitive bias and executive function involving mental flexibility and response inhibition in IAD.Methodology/Principal FindingsA total of 46 subjects who met the criteria of the modified Young’s Diagnostic Questionnaire for Internet addiction (YDQ) were recruited as an Internet game addiction (IGA) group, along with 46 healthy control individuals. All participants performed the Internet game-shifting task. Using hit rate, RT, d′ and C as the dependent measures, a three-way ANOVA (group × target × condition) was performed. For hit rate, a significant effect of group, type of target and condition were found. The group–target interaction effect was significant. For RT, significant effects were revealed for group and type of target. The group–target interaction effect was significant. Comparisons of the means revealed that the slowing down of IGA relative to NIA was more pronounced when the target stimuli were neutral as opposed to Internet game-related pictures. In addition, the group–condition interaction effect was significant. For d′, significant effects of group, type of target and condition were found. The group–target interaction effect was significant. For C, the type of target produced a significant effect. There was a positive correlation between the length of the addiction (number of years) and the severity of the cognitive bias.ConclusionsIGA present cognitive biases towards information related to Internet gaming. These biases, as well as poor executive functioning skills (lower mental flexibility and response inhibition), might be responsible for Internet game addiction. The assessment of cognitive biases in IGA might provide a methodology for evaluation of therapeutic effects.