Tilpisertib (GS-4875) is a potent, highly selective TPL2 kinase (COT, MAP3K8) inhibitor with IC50 of 1.3 nM, with no significant off-target binding activity.
Tilpisertib (GS-4875) selectively inhibited LPS and TNFα-stimulated phosphorylation of TPL2, MEK, and ERK, with little to no inhibition of phosphorylated p38, JNK or p65.
Tilpisertib (GS-4875) similarly inhibited in the RNA production and secretion of TNFα, IL-1β, IL-6, and IL-8 following LPS stimulation in primary human monocytes.
Tilpisertib (GS-4875) inhibited the secretion of TNFα and IL-6 following LPS stimulation in monocyte-derived dendritic cells.
Tilpisertib (GS-4875) reduced TNFα-stimulated pERK with no effect on ERK activation downstream of EGF in A431 cells stimulated with either TNFα or EGF.
Tilpisertib (GS-4875) treatment showed dose and exposure dependent inhibition (IC50=667 nM) of LPS-stimulated TNFα production a rat LPS-TNFα model of acute inflammation.