2-[5-Chloro-2-[[3-(4-methylpiperazin-1-yl)propyl]amino]pyrimidin-4-yl]benzo[b]thiophene-4-carboxamide N-cyclopropyl Trihydrochloride is an inhibitor of IkB-kinase (IKK2). Small molecules that inhibits IkB-kinase and NF-κB pathways are potential anti-inflammatory drug candidate.
ly2409881 is a potent and selective inhibitor of ikk2 with ic50 value of 30 nm [1].iκb kinase β (ikk2) is an enzyme that serves as a subunit of iκb kinase, which is involved in the cytokine-activated immune responses. ikk2 activates nuclear factor kappa-b kinase (nf-κb).ly2409881 is a selective ikk2 inhibitor and exhibited >10-fold selectivity over other common kinases and ikk1. in the ovarian cancer cell line skov3, ly2409881 showed moderate cytotoxicity. while coadministration of ly2409881 and tnfɑ significantly induced cells death, which suggested ly2409881 inhibited nf-κb mediated antiapoptotic signals in a tnfɑ-dependent way. in the dlbcl cell line ly10, ly2409881 (10 μm) inhibited tnfɑ-dependent phosphorylation of iκb. in the dlbcl cell line sudhl2, ly2409881 (10 μm) inhibited the nuclear signals of p50 and nf-κb. also, ly2409881 induced apoptosis in a concentration-dependent way [1].in scid-beige mice bearing ly10 cell-derived tumors, ly2409881 (50, 100 and 200 mg/kg) significantly inhibited tumor growth [1].
A well-established xenograft model of DLBCL is used to confirm the activity of LY2409881 in vivo. SCID-beige mice implanted with LY10 cell-derived tumors are given intraperitoneal injections of LY2409881 twice weekly at three different doses: 50, 100, and 200 mg/kg. The treatments are well tolerated, resulting in no death or severe morbidity of the mice. The average tumor volume is graphed as a function of time for each treatment group. The rates of tumor volume growth of the treatment groups are all significantly slower than the untreated control group (P≤0.01)[1].
[1]. deng c, lipstein m, rodriguez r, et al. the novel ikk2 inhibitor ly2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of nf-κb. clin cancer res, 2015, 21(1): 134-145.
