BV6 is an IAP antagonist with Kd values of o.46nM and 1.3nM for c-IAP and XIAP, respectively. Treatment with BV-6 could cause time (5μM, 2-60min)-dependent c-IAP1 and c-IAP2 ubiquitin degradation in MDA-MB-231 cells. The loss of XIAP can be observed at 8h post treatment. BV-6 led induced caspase-dependent cell death in EVSAT and A2058 cells at concentration ranging in 8-1000nM for 24h concentration-dependently, as well as cell death in MDA-MB-231 at concentration<20nM. And this cell death by BV-6 was TNF dependent. BV-6 at 5μM induced a 15- to 30-fold increase in TNFα mRNA levels and further activated its downstream, both of canonical and noncanonical NF-κB pathways, as the phosphorylation and subsequent proteasomal degradation of IκB, time-dependent increased p52 and p100 and inhibited destabilization of NIK by BV-6 can be observed[1]. After treatment with 10mg/kg BV6, i.p., for 4 weeks could significantly reduce the total number of lesions, the average weight and the surface area of lesions in endometriosis-like model[2].
作用机制
BV-6 can bind to the BIR domains of IAP proteins and then lead to rapid ubiquitination and proteasomal degradation of cIAPs.[1]
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