产品描述:
Dapansutrile is a potent, selective and orally active inhibitor of the NLRP3 inflammasome. It directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 adenosine triphosphatase (ATPase) activity, resulting in the suppression of NLRP3 inflammasome assembly (interaction between NLRP3, Asc and caspase-1) and activation. Dapansutrile is an anti-inflammatory agent by inhibiting the release of inflammatory signals such as IL-1beta and IL-18. However, it does not impact the mRNA levels of the NLRP3, Asc, caspase-1, IL-1beta and IL-18 genes. In vitro, nanomolar concentrations of Dapansutrile reduce IL-1beta and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. Dapansutrile is selective for NLRP3 over NLRP4 and AIM2 inflammasomes at concentrations up to 100µM. Known other targets of Dapansutrile include several phosphorylated kinases such as Src, Fyn, HcK and STAT3. Dapansutrile has a preferable toxicological safety profile for in vivo studies. Dapansutrile reduces myeloperoxidase (MPO), CXCL1 and IL-6 levels in peritoneal fluid as well as IL-1beta levels in liver, lung, spleen and skeletal muscle in a mouse model of LPS-induced systemic inflammation. It reduces joint swelling and markers of inflammation in synovial fluid in a mouse model of acute arthritis and displays cardioprotective effects in a mouse model of cardiac ischemic reperfusion injury and it rescues cognitive impairment in a mouse model of Alzheimer's disease. Dapansutrile reduces IL-1beta release in blood monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), an autoinflammatory disorder characterized by gain-of-function mutations in NLRP3. Dapansutrile was tested in clinical trials and has been proposed as a beneficial compound for the remedy of osteoarthritis and gouty arthritis. In addition, preclinical research has proposed Dapansutrile to be potentially beneficial for heart failure and multiple sclerosis. Dapansutrile inhibits tumor-derived NLRP3 to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression.