AMG 548

AMG 548 is a potent and selective inhibitor of p38α with IC50 values of 0.5, 3.6, 2600 and 4100 nM for p38α, p38β, p38γ and p38δ, respectively.

P38 mitogen-activated protein kinase (p38) is a serine/threonine kinase and is responsive to a variety of cellular stresses including inflammatory cytokines, osmotic shock, ultraviolet light, lipopolysaccharides (LPS) and growth factors. P38α kinase involved in the biosynthesis of TNFα and IL-1β at the transcriptional and translational level [1][2].

AMG 548 is a potent and selective p38α inhibitor. In the antagonistic enzyme fragment complementation (EFC) and β-catenin-driven luciferase (SuperTOPflash) reporter gene assays, AMG 548 inhibited Wnt/β-catenin signaling, which was due to cross-reactivity with another kinase. AMG 548 inhibited 17 kinases by more than 80%. In U2OS-EFC cells, AMG 548 inhibited CKIδ and CKIε, which played an important role in the activation of Wnt/b-catenin signaling. Also, the concentration of AMG 548 needed to inhibit CKIδ/ε in cells was closely approximate that required to inhibit Wnt/b-catenin signaling in the EFC and TOPflash assays, which suggested AMG 548 inhibited Wnt/b-catenin signaling mediated by the inhibition of CKIδ/ε [3].

References:
[1].  Dominguez C, Powers DA, Tamayo N. p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel, 2005, 8(4): 421-430.
[2].  Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem, 2005, 12(25): 2979-2994.
[3].  Verkaar F, van der Doelen AA, Smits JF, et al. Inhibition of Wnt/β-catenin signaling by p38 MAP kinase inhibitors is explained by cross-reactivity with casein kinase Iδ/ɛ. Chem Biol, 2011, 18(4): 485-494.

MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein.[Pubmed:16378500]

Curr Med Chem. 2005;12(25):2979-94.

Mitogen-activated protein kinase p38 is a serine/threonine kinase originally isolated from lipopolysaccharide (LPS) stimulated monocytes. There are four isoforms p38alpha p38beta, p38gamma, and p38delta. The most thoroughly studied isoform is p38alpha, whose activation has been observed in many hematopoietic and non-hematopoietic cell types upon appropriate stimuli. Subsequently, p38alpha kinase has been shown to be involved in the biosynthesis of TNFalpha and IL-1beta at the translational and transcriptional level. MAP kinase p38alpha represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. The discovery and publication of p38alpha and the pyridinyl-imidazole inhibitor initiated a huge effort by many companies to develop p38alpha inhibitors as potential treatment for inflammatory diseases. Herein we provide a brief overview of recent reported clinical results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO 323. However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature.

p38 MAP kinase inhibitors: many are made, but few are chosen.[Pubmed:16022178]

Curr Opin Drug Discov Devel. 2005 Jul;8(4):421-30.

The mitogen-activated protein kinase (MAPK) p38 is a Ser/Thr kinase, originally isolated from lipopolysaccharide-stimulated monocytes. There are four isoforms of the enzyme (p38alpha, p38beta, p38gamma and p38delta), which differ in tissue distribution, regulation of kinase activation and subsequent phosphorylation of downstream substrates. These enzymes also differ in sensitivity to p38 MAPK inhibitors. The most thoroughly studied isoform is p38alpha, for which activation has been observed in many hematopoietic and non-hematopoietic cell types upon appropriate stimuli. p38alpha kinase is involved in the biosynthesis of the cytokines tumor necrosis factor-alpha and interleukin-1beta at the translational and transcriptional level. MAPK p38alpha represents a point of convergence for multiple signaling processes that are activated during inflammation, making it a key potential target for the modulation of cytokine production. The discovery and publication of p38alpha and a pyridinyl-imidazole-based p38alpha inhibitor initiated a huge effort by many companies to develop p38alpha inhibitors as potential treatments for inflammatory diseases. Herein, a brief overview is provided of the discovery and development of AMG-548 (Amgen Inc), a selective and efficacious p38alpha inhibitor, and its pharmacodynamic effects in a first-in-human study. Data from a phase I multidose clinical trial are also included. In addition, other p38alpha inhibitors that have advanced to clinical trials over the last three years are discussed, such as BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), SCIO-469 and SCIO-323 (Scios Inc), and VX-702 (Vertex Pharmaceuticals Inc/Kissei Pharmaceutical Co).

AMG-548, an orally active and selective p38α inhibitor (Ki=0.5 nM), shows slightly selective over p38β (Ki=36 nM) and >1000 fold selective against p38γ and p38δ. AMG 548 is also extremely potent in the inhibition of whole blood LPS stimulated TNFα (IC50=3 nM). AMG-548 inhibits Wnt signaling by directly inhibiting Casein kinase 1 isoforms δ and ε.

AMG 548,864249-60-5,Natural Products,p38, buy AMG 548 , AMG 548 supplier , purchase AMG 548 , AMG 548 cost , AMG 548 manufacturer , order AMG 548 , high purity AMG 548