PH-797804

PH-797804 is a novel pyridinone inhibitor of p38α with IC50 of 26 nM; 4-fold more selective versus p38β and does not inhibit JNK2.IC50 value: 26 nM [1]Target: p38αMAPKin vitro: PH-797804 blocks LPS-induced TNF-α production and p38 kinase activity in the human monocytic U937 cell line, with comparable IC50 of 5.9 nM and 1.1 nM. PH-797804 has no inhibitory effect on either the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells at concentrations up to 1 μM. PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner, with IC50 of 3 nM in primary rat bone marrow cells [1]. IC50 values for PH-797804 against the following targets have been determined to be greater than 200 μM (unless specified): CDK2, ERK2, IKK1, IKK2, IKKi, MAPKAP2, MAPKAP3, MKK7 (>100 μM), MNK, MSK (>164 μM), PRAK, RSK2, and TBK1, which means the activity of PH-797804 is specific [2]. in vivo: Orally dosing of PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. PH-797804 treatment for 10 days demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Dose-response analysis resulted in ED50 values of 0.07 mg/kg and 0.095 mg/kg in rat and cynomolgus monkeys, respectively. PH-797804 inhibits LPS-induced TNF-α, IL-6, and MK-2 activity in a dose- and concentration-dependent manner in a human endotoxin challenge model [1].

Signaling Pathways >> MAPK/ERK Pathway >> p38 MAPK

Research Areas >> Inflammation/Immunology

[1]. Hope HR, et al. Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation. J Pharmacol Exp Ther, 2009, 331(3), 882-895.

[2]. Xing L, et al. Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804. Biochemistry, 2009, 48(27), 6402-6411.

SB203580 | SB202190 (FHPI) | Doramapimod (BIRB 796) | LY2228820 | SB 239063 | Losmapimod | PD 169316 | Talmapimod | Tat-NR2B9c | Dehydrocorydaline chloride | TAK-715 | VX 702 | VX-745 | SKF 86002 | Acumapimod