Entrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7

Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke

“…Several studies have indicated that oxidative stress also enhances NLRP3 inflammasome activation 49 , 50 , 51 , 52 , 53 ; thus, we investigated whether the inhibitory effects of CMPK2 knockdown on NLRP3 inflammasome activation were reliant on ROS generation. However, we found that CMPK2 knockdown did not change the level of mtROS production in primary microglial cells after LPS plus ATP stimulation ( Figures S8 A and S8B).…”

Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis

“…It is promising to develop inhibitors that interfere with the NLRP3-NEK7 interaction to inhibit the formation of the NLRP3 inflammasome. Although there has been controversy in recent years regarding the necessity of the NEK7-NLRP3 interaction for NLRP3 inflammasome activation in human cells, many studies have shown that certain molecules can inhibit NLRP3 inflammasome activation by interfering with the NEK7-NLRP3 interaction, thus exhibiting anti-inflammatory activity. , For example, Entrectinib (ENB) directly targets NEK7 to inhibit NLRP3 inflammasome activation, thereby treating inflammatory diseases . Additionally, several small molecule drugs that target NEK7 to disrupt the NLRP3-NEK7 interaction have entered clinical trials, such as HT-6184, Berberine, and MRT-3483 .…”

“…NEK7 disrupts its inactive cage-like structure of NLRP3 inflammasome through interaction with the LRR domain . While several compounds, such as HT-6184, Berberine, and MRT-3483, have been reported to inhibit NLRP3 inflammasome formation by interfering with the NLRP3-NEK7 interaction, none of these molecules have been shown to function by targeting the LRR domain of the NLRP3 protein. To date, there have been no reports of compounds that can inhibit NLRP3 inflammasome activation by specifically targeting the LRR domain of the NLRP3 protein.…”