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].
Doramapimod/达马莫德 细胞实验
Cell Line
Concentration
Treated Time
Description
References
FA-iPSCs
5 μM
1 week
Doramapimod significantly improved the derivation of CD34+/CD43+ progenitors from FA-iPSCs, particularly in the CD34hi/CD43lo population.
Nat Commun. 2014 Jul 7;5:4330.
NK cells
0.05 – 1μM
Overnight
Restoration of NK cell function and metabolic profile, particularly through p38 inhibition, significantly enhanced TNF-α and CD107a expression and improved mitochondrial function and autophagy capacity
Front Immunol. 2022 May 23;13:875072.
PANC-1
5 µM
24 h
To evaluate the effect of Doramapimod on RSL3-induced cell death, results showed that Doramapimod significantly reduced cell death.
Nat Commun. 2024 Oct 2;15(1):8540.
BxPC3
5 µM
24 h
To evaluate the effect of Doramapimod on RSL3-induced cell death, results showed that Doramapimod significantly reduced cell death.
Nat Commun. 2024 Oct 2;15(1):8540.
NP-1 and AF-1 cells
40 nM
6 h
Inhibition of p38 kinase, reduction of pRunx2 phosphorylation, and suppression of ADAMTS gene expression
Biol Direct. 2023 Jul 6;18(1):37.
MRC-5 human lung fibroblasts
10 µM
72 h
Doramapimod inhibited Mtb-induced cell death as effectively as dexamethasone.
Nat Commun. 2019 Feb 8;10(1):688.
J774 mouse macrophages
10 µM
48 h
Doramapimod inhibited Mtb-induced cell death as effectively as dexamethasone.
Nat Commun. 2019 Feb 8;10(1):688.
human Mφ isolated from healthy donors
10 µM
48 h
Doramapimod inhibited Mtb-induced cell death as effectively as dexamethasone.
Nat Commun. 2019 Feb 8;10(1):688.
human Mφ isolated from treatment naïve TB patients
10 µM
48 h
Doramapimod inhibited Mtb-induced cell death as effectively as dexamethasone.
To investigate the inhibitory effect of Doramapimod on p38MAPK phosphorylation, results showed that Doramapimod counteracted the effects of mycobacterial infection and HRH1 on p47phox phosphorylation
mBio. 2022 Oct 26;13(5):e0200422.
Doramapimod/达马莫德 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NMRInu/nu mice
PANC-1 xenograft model
Oral
50 mg/kg
Twice weekly until the end of the experiment
To evaluate the effect of Doramapimod on gemcitabine treatment, results showed that Doramapimod significantly increased tumor resistance to gemcitabine.
Nat Commun. 2024 Oct 2;15(1):8540.
Mice
Chronic inflammation model
Intraperitoneal injection
4 mg/kg
Once a week for 6 weeks
Inhibition of p38 kinase, reduction of pRunx2 phosphorylation, and suppression of ADAMTS gene expression, thereby slowing intervertebral disc degeneration
Biol Direct. 2023 Jul 6;18(1):37.
C57BL/6 mice
Mtb-infected peritoneal Mφ
Intraperitoneal injection
100 mg/kg
Once daily for 3 days
Doramapimod significantly protected peritoneal macrophages from Mtb-induced cell death.
Nat Commun. 2019 Feb 8;10(1):688.
Nude mice
A375 cell subcutaneous tumor model
Oral
10 mg/kg
Twice a week for 38 days
Doramapimod combined with Bortezomib significantly enhanced antitumor activity, but also accompanied by obvious weight loss
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