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Chemical Structure| 285983-48-4 Chemical Structure| 285983-48-4

Structure of Doramapimod
CAS No.: 285983-48-4

Chemical Structure| 285983-48-4

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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.

Synonyms: BIRB 796

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Product Citations

Product Citations

Zhang, Chenliang ; Huang, Chen ; Xia, Hongwei ; Xu, Huanji ; Tang, Qiulin ; Bi, Feng

Abstract: Aggresome formation is a protective cellular response to counteract proteasome dysfunction by sequestering misfolded proteins and reducing proteotoxic stress. Autophagic degradation of the protein aggregates is considered to be a key compensating mechanism for balancing proteostasis. However, the precise role of autophagy in proteasome inhibition-induced aggresome biogenesis remains unclear. Herein, we demonstrate that in the early stage of proteasome inhibition, the maturation of the autophagosome is suppressed, which facilitates aggresome formation of misfolded proteins. Proteasome inhibition-induced phosphorylation of SQSTM1 T269/S272 inhibits its autophagic receptor activity and promotes aggresome formation of misfolded proteins. Inhibiting SQSTM1 T269/S272 phosphorylation using Doramapimod aggravates proteasome inhibitor-mediated cell damage and tumor suppression. Taken together, our data reveal a negative effect of autophagy on aggresome biogenesis and cell damage upon proteasome inhibition. Our study suggests a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment.

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Product Details of Doramapimod

CAS No. :285983-48-4
Formula : C31H37N5O3
M.W : 527.66
SMILES Code : O=C(NC1=C2C=CC=CC2=C(OCCN3CCOCC3)C=C1)NC4=CC(C(C)(C)C)=NN4C5=CC=C(C)C=C5
Synonyms :
BIRB 796
MDL No. :MFCD09752957
InChI Key :MVCOAUNKQVWQHZ-UHFFFAOYSA-N
Pubchem ID :156422

Safety of Doramapimod

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P264-P270-P301+P312-P330-P501

Related Pathways of Doramapimod

MAPK
TLR

Isoform Comparison

Biological Activity

Target
  • JNK2

  • p38α

    p38α, IC50:38 nM

    p38α, Kd:0.1 nM

In Vitro:

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. Nat Commun. 2019 Feb 8;10(1):688.
AD293 cells 50 μM 14 h Inhibits SQSTM1 (T269/S272) phosphorylation, reducing aggresome formation Cell Death Dis. 2022 Jul 15;13(7):615.
A375 cells 50 μM 14 h Inhibits SQSTM1 (T269/S272) phosphorylation, reducing aggresome formation Cell Death Dis. 2022 Jul 15;13(7):615.
MDA-MB-231 cells 50 μM 14 h Inhibits SQSTM1 (T269/S272) phosphorylation, reducing aggresome formation Cell Death Dis. 2022 Jul 15;13(7):615.
THP-1 macrophages 10 µM 24 h 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.

In Vivo:

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 Cell Death Dis. 2022 Jul 15;13(7):615.

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT02208856 Healthy Phase 1 Completed - -
NCT02211170 Healthy Phase 1 Completed - -
NCT02209831 Healthy Phase 1 Completed - -
NCT02209779 Arthritis, Rheumatoid Phase 2 Completed - -
NCT02209792 Crohn Disease Phase 2 Terminated - -
NCT02211157 Healthy Phase 1 Completed - -
NCT02211144 Healthy Phase 1 Completed - -
NCT02209753 Psoriasis Phase 2 Completed - -
NCT02214888 Arthritis, Rheumatoid Phase 2 Terminated - -
NCT02211885 Healthy Phase 1 Completed - -
NCT02209805 Healthy Phase 1 Completed - -

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

1.90mL

0.38mL

0.19mL

9.48mL

1.90mL

0.95mL

18.95mL

3.79mL

1.90mL

References

 

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