SMI-6860766

SMI-6860766 is an inhibitor of the protein-protein interaction between TNF receptor-associated factor 6 (TRAF6) and CD40. It binds to TRAF1, TRAF2, TRAF3, and TRAF6 (Kds = 52, 30, 37, and 59 µM, respectively). SMI-6860766 inhibits LPS-induced increases in the levels of NF-κB in RAW 264.7 macrophages (IC50 = 0.3 µM). It inhibits anti-Cd40 antibody-induced increases in the levels of Il-1β and Il-6 in primary mouse bone marrow-derived macrophages (BMDMs; IC50s = 5.7 and 2.4 µM, respectively). SMI-6860766 (10 µmol/kg) increases survival in a mouse model of sepsis induced by cecal ligation and puncture. It decreases blood levels of glucose and adipose tissue levels of leukocytes, T helper cells (Ths), cytotoxic T cells, and M1 and M2 macrophages in a mouse model of diet-induced obesity (DIO) when administered at a dose of 10 µmol/kg per day.