The mitogen-activated protein kinase (MAPK) p38a is activated by environmental stimuli, bacterial products and cytokines. It plays a critical role in the production of proinflammatory cytokines such as TNF-a and IL-1b. They comprise p38α, p38β, SAPK3/p38γ (also known as ERK6), and SAPK4/p38δ. Each p38 isoform may have different biological functions and different physiological substrates. But they all phosphorylate substrates containing the minimal consensus sequence Ser/Thr-Pro. Specific inhibitors of these enzymes could facilitate the identification of physiological substrates for p38 isoforms.

The compound Doramapimod (BIRB 796) is one of the most potent compounds of this diaryl urea series and binds to p38α with both slow association and dissociation rates.

Additionally, BIRB796 inhibits p38α by a novel mechanism, indirectly competing with the binding of ATP. Structure determination revealed that, prior to binding, the kinase undergoes a reorganization of the activation loop exposing a critical binding domain and yielding a structure incompatible with ATP binding. BIRB796 demonstrated efficacy in an endotoxin (lipopolysaccharide)-stimulated mouse model of tumor necrosis factor-α production and in a mouse model of established collagen-induced arthritis. BIRB796 also displayed anti-inflammatory effects in a trial of human endotoxemia and has recently been in phase IIb/III clinical trials for the treatment of rheumatoid arthritis. Yvonne et al found that BIRB 796 inhibits all four SAPK/p38s isoforms in vitro.

Gruenbaum et al found that BIRB796 reverses ABCB1-mediated MDR by directly inhibiting its transport function. Jin et al found that Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. To sum up, these findings may be useful for cancer combinational therapy with BIRB796 in the clinic.

Dietrich J, et al. The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors. Bioorg Med Chem. 2010 Aug 1;18(15):5738-48
Gruenbaum LM, et al. Inhibition of pro-inflammatory cytokine production by the dual p38/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling. Biochem Pharmacol. 2009 Feb 1;77(3):422-32.