For research use only. Not Intended for Therapeutic Use!
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b-AP15(NSC687852) is a specific inhibitor of the deubiquitinating enzymes UCHL5 and Usp14 of the 26S proteasome. It blocks the deubiquitinating activity of the 26S proteasome.
in vitro: b-AP15 abrogates the deubiquitinating activity of the 19S regulatory particle.b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2 . b-AP15 triggers time- and dose-dependent apoptosis of the human multiple myeloma (MM) cell lines RPMI8226 and U266, as determined by phosphatidylserine exposure. Apoptosis was dependent on caspase activation and was partially dependent on cathepsin D. Furthermore, b-AP15 triggered processing of pro-caspase-3 and cleavage of poly (ADP-ribose) polymerase in MM cells. b-AP15 also induced caspase-independent apoptosis in primary human natural killer cells . in addition to inhibition of deubiquitinases, b-AP15 inhibits the selenoprotein thioredoxin reductase (TrxR) .
in vivo: Treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model . b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with suberoylanilide hydroxamic acid, lenalidomide, or dexamethasone induces synergistic anti-MM activity in distinct human MM xenograft models .