LY2409881 is a selective inhibitor of IκB kinase β (IKK2) with an IC50 of 30 nM.

IKK2:30 nM (IC50)

LY2409881, an IKK2 inhibitor, effectively blocks the TNFα-induced activation of NF-κB, focusing on its role in inhibiting the kinase activity of IKK2 with a potent IC50 of 30nM, while showing significantly less inhibition on IKK1 and other kinases. Its specificity for NF-κB signaling pathways was explored through cell-based assays, investigating its impact on the antiapoptotic functions triggered by TNFα, a known activator of NF-κB. Particularly in the SKOV3 ovarian cancer cell line, LY2409881 displayed moderate cytotoxicity alone; however, its combination with TNFα significantly enhanced cell death. This increased cytotoxic effect is attributed to LY2409881's blocking of the TNFα-induced NF-κB-mediated antiapoptotic signaling, without affecting the TNFα-activated proapoptotic pathways involving TRADD and FADD.

In a recognized DLBCL xenograft model, the in vivo efficacy of LY2409881 is validated. LY10 cell-derived tumors in SCID-beige mice are treated with bi-weekly intraperitoneal doses of LY2409881 at 50, 100, and 200 mg/kg. These treatments demonstrate a favorable tolerability profile, causing neither mortality nor severe morbidity among the mice. Tumor volume growth rates, graphed over time, reveal all LY2409881-treated groups exhibit significantly slower tumor progression compared to the untreated control group (P≤0.01)[1].