The p38 MAPK pathway is a key regulatory factor for the biosynthesis of pro-inflammatory cytokines at the transcription and translation levels. There are four splicing variants in the p38 family: p38 α, P38 β, P38 γ (ERK6, SAPK3) and p38 δ (SAPK4). The MAPK pathway is an intracellular signaling pathway that can regulate various cellular processes. Nonetheless, it consists of three pathways, involving ERK1/2, JNK1/2/3, and the p38 MAPK signaling pathway. Specifically, this makes the different components of the pathway potential targets for treating autoimmune and inflammatory diseases. Importantly, p38 regulates various cellular functions, such as metabolism, secretion, migration, differentiation, apoptosis, and aging.

Besides, JNKs and p38 MAPKs function in a cell environment-specific and cell type-specific manner. They play an important role in coordinating the signaling mechanisms of various stress responses in cells. Moreover, they also control the proliferation, differentiation, survival, and migration of specific cell types. Furthermore, the regulation of the p38 pathway is not an isolated cascade, and many different upstream signals can lead to p38 activation. Today, we will introduce an orally active p38 inhibitor for inflammation research, SX-011.

SX 011 is an Orally Active p38 Inhibitor for Inflammation Research.

To begin with, SX 011 is a p38 inhibitor with IC₅₀s of 9 nM and 90 nM against p38α and p38β, respectively. In particular, SX 011 also inhibits JNK-2 with an IC₅₀ of 100 nM. SX-011 is orally bioavailable.

Secondly, SX-011 inhibits LPS stimulated TNFα and interleukin-1β (IL-1β) from human peripheral blood mononuclear cells (PBMC) with an IC₅₀ of 200 nM and 900 nM, respectively. Additionally, IL-6 (IC₅₀ 250 nM) and IL-8 (IC₅₀ 100 nM) are significantly inhibited in this assay.

Taken together, SX-011 is orally bioavailable in preclinical species (rat, 24%; monkey, 29%; dog, 43%). Obviously, SX-011 has demonstrated efficacy in both acute and chronic models of inflammation in rats. Rat t_1/2 = 30 min.

All in all, SX 011 is an orally active p38 inhibitor for inflammation research.

References:

[1] Hynes J Jr, et al. Curr Top Med Chem. 2005;5(10):967-85.