PS-1145

431898-65-6

C17H11ClN4O

DMSO : >= 43 mg/mL (133.23 mM); H2O : < 0.1 mg/mL (insoluble)

NF-kappaB

PS-1145 is an IkappaB kinase (IKK) inhibitor with an IC₅₀ of 88 nM. IC50 & Target: IC50: 88 nM (IKK)^[1] In Vitro: PS-1145 blocks TNFalpha-induced NF-kappaB activation in a dose- and time-dependent fashion in MM cells through inhibition of IkappaBalpha phosphorylation. Dexamethasone (Dex), which up-regulates IkappaBalpha protein, enhances blockade of NF-kappaB activation by PS-1145. PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFalpha-induced intracellular adhesion molecule (ICAM)-1 expression on both RPMI8226 and MM.1S cells is also inhibited by PS-1145. Moreover, PS-1145 inhibits both IL-6 secretion from bone marrow stromal cells (BMSCs) triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs^[1]. In Vivo: Administration of either Bortezomib or PS-1145 (50 mg/kg) results in a significant decrease in serum levels of all 3 cytokines that is nonsignificantly different from those in mice that underwent transplantation with TCD BM alone^[2]. PS1145 is injected intracerebroventricular (icv) as a pretreatment to block hypothalamic inflammation induced by IL-4 in adult male Wistar rats consuming a high-fat diet (HFD) over an 11-day period. The four groups of rats according to icv pretreatment/treatment condition are Veh/Veh, Veh/IL-4, PS1145/Veh, and PS1145/IL-4. Rats in the Veh/IL-4 group display increased weight gain on the HFD compared with the Veh/Veh group (P<0.05 on days 6-9). Importantly, the effect of icv IL-4 administration to increase body fat mass during high-fat (HF) feeding is completely blocked by icv PS1145 pretreatment at a dose that has no independent effect on body composition (on day 8: P<0.001, PS1145/Veh vs. PS1145/IL-4; P=not significant, PS1145/Veh vs. Veh/Veh). In PS1145/IL-4 injected rats, IL-1beta mRNA content is decreased by ca.75% compared with that of Veh/IL-4-injected rats^[3].