ralimetinib   Click here for help

GtoPdb Ligand ID: 7959

Synonyms: LY-2228820 | LY-2228820 free base | LY2228820
PDB Ligand
Compound class: Synthetic organic
Comment: Ralimetinib was developed as a potent and selective, ATP-competitive inhibitor of p38 MAPK α and β (MAPK14 and MAPK11 respectively) [3,6]. The compound is delivered orally as the dimesylate salt (PubChem CID 11570805). It is compound 40 in Mader et al. (2008) [4].
In 2023, a report in Cell Chemical Biology demonstrated that the anticancer activity of ralimetinib is in fact due to inhibition of EGFR function, despite the compound being >30-fold less potent against EGFR than it is against p38α [1]. This study found that sensitivity of tumour cells to ralimetinib was retained when p38α and p38β genes were knocked-out, and that the EGFRT790M (gatekeeper) mutation conferred resistance to both ralimetinib and the approved EGFR inhibitor gefitinib. The cocrystal structure of ralimetinib bound to the EGFR confirmed the EGFR hypothesis.

SARS-CoV-2: p38 MAPK activity has been reported to be upregulated following SARS-CoV-2 infection of host cells in vitro. Ralimetinib produces an antiviral effect with an IC50 of 873 nM [2].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 4
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 85.41
Molecular weight 420.24
XLogP 5.63
No. Lipinski's rules broken 1
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Canonical SMILES Fc1ccc(cc1)c1nc([nH]c1c1ccc2c(n1)n(CC(C)(C)C)c(n2)N)C(C)(C)C
Isomeric SMILES Fc1ccc(cc1)c1nc([nH]c1c1ccc2c(n1)n(CC(C)(C)C)c(n2)N)C(C)(C)C
InChI InChI=1S/C24H29FN6/c1-23(2,3)13-31-20-17(28-22(31)26)12-11-16(27-20)19-18(14-7-9-15(25)10-8-14)29-21(30-19)24(4,5)6/h7-12H,13H2,1-6H3,(H2,26,28)(H,29,30)
Bioactivity Comments
LY2228820 effects significant tumour growth inhibition in multiple cancer models in vivo, including those for melanoma, non-small cell lung cancer, ovarian cancer, glioma, myeloma and breast cancer [3].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
mitogen-activated protein kinase 11 Hs Inhibitor Inhibition 9.0 pIC50 - 1
pIC50 9.0 (IC50 1x10-9 M) [1]
mitogen-activated protein kinase 14 Hs Inhibitor Inhibition 8.1 – 8.4 pIC50 - 1,4
pIC50 8.4 (IC50 4x10-9 M) [1]
pIC50 8.1 (IC50 7x10-9 M) [4]
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
epidermal growth factor receptor Hs Inhibitor Inhibition 5.2 – 8.0 pIC50 - 1
pIC50 8.0 (IC50 1.1x10-8 M) [1]
Description: Inhibitor potency for EGFRG719C
pIC50 6.7 (IC50 1.8x10-7 M) [1]
Description: Inhibitor potency for WT EGFR
pIC50 5.2 (IC50 6.06x10-6 M) [1]
Description: Inhibitor potency for EGFR with gatekeeper mutation T790M