tcsc1630 LCL161

LCL161 is a novel IAP inhibitor, inhibits XIAP activity in HEK293 cell with IC₅₀ of 35 nM, also inhibits cIAP1 activity in MDA-MB-231 cell with IC₅₀ of 0.4 nM.

IC50 & Target: IC50: 35 nM (XIAP, in HEK293 cell), 0.40 nM (cIAP1, in MDA-MB-231)^[1]

In Vitro: LCL161 shows anti-proliferative effects and reduces cell viability significantly in Hep3B (IC₅₀=10.23 μM) and PLC5 (IC₅₀=19.19 μM) cells in a dose-dependent manner. LCL161 induces apoptosis significantly in both the sensitive cell lines in a dose-dependent manner. LCL161 significantly down regulates the expression of cIAP1, starting at very low concentrations. LCL161 at low concentrations inhibits cIAP1 starting at the concentration of 0.5 nM^[2]. LCL161 is a small molecule oral IAP antagonist in development for use in combination with cytotoxic agents. The effect of LCL161 on CYP3A4/5 (CYP3A) activity is investigated in vitro. Results in human liver microsomes indicated LCL161 inhibited CYP3A in a concentration- and time-dependent manner (K_I of 0.797 µM and K_inact of 0.0803 min^-1). LCL161 activates human PXR in a reporter gene assay and induced CYP3A4 mRNA up to ~5-fold in human hepatocytes^[3].

In Vivo: Tumor-bearing mice are treated with vehicle or LCL161 p.o. at a dose of 50 mg/kg/day, or SC-2001 p.o. at a dose of 10 mg/kg/day, 5 days a week, or in combination for the duration of the study. Tumor growth is significantly inhibited by co-treatment with SC2001 and LCL161 and tumor size in the co-treatment group is only one third of that of the control group at the end of the study^[2]. LCL161 is a first-in-class oral Smac mimetic shown to induce degradation of cIAP1 and cleavage of caspase 3 in mouse xenograft models^[4].