Doramapimod is a highly selective p38α MAPK inhibitor with Kd of 0.1 nM, 330-fold greater selectivity versus JNK2, weak inhibition for c-RAF, Fyn and Lck, insignificant inhibition of ERK-1, SYK, IKK2, ZAP-70, EGFR, HER2, PKA, PKC, PKCα/β/γ.
The stress-activated protein kinase (SAPK) p38 isoforms are mitogen-activated protein kinase (MAPK) family members. MAPKs act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The well reported isoforms of p38 MAPKs include p38α, p38β and others.
Doramapimod, also termed BIRB 796, is a p38 MAPK inhibitor. The IC50s of doramapimod against p38α determined by kinase assay at incubation time of 0 min, 30 min and 90 min were 0.08 μM, 0.07 μM and 0.038 μM, respectively, and the data of doramapimod against p38β were 0.38 μM, 0.215 μM and 0.065 μM, respectively at the same time points[3]. The affinity of doramapimod for p38 MAPK was 0.1 nM, and the inhibitory IC50 of it against TNFα in THP-1 cell culture was 18 nM[4]. In multiple myeloma MM1S and U266 cells, 2h treatment by doramapimod at the concentration of 25 nM was sufficient to inhibit phosphorylation of p38 MAPK[5].
In a mouse model of LPS-stimulated TNF-α synthesis, a 65% inhibition of TNF-α synthesis was observed when doramapimod was dosed orally at 10 mg/kg. In a 5 week model of established collagen-induced arthritis using B10.RIII mice, doramapimod produced a 63% inhibition of arthritis severity when dosed orally at 30
mg/kg qd[6].
作用机制
Doramapimod is a p38 MAPK inhibitor. Doramapimod indirectly competed with the binding of ATP, but prior to binding, the kinase underwent a reorganization of the activation loop exposing a critical binding domain and yielded a structure incompatible with ATP binding[4].
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