RIPK1 inhibitor 22b   Click here for help

GtoPdb Ligand ID: 10155

Synonyms: compound 22b [PMID: 30480444]
Compound class: Synthetic organic
Comment: Compound 22b represents a novel chemical scaffold class for receptor-interacting protein kinase 1 (RIPK1) inhibitors [1]. It has shown anti-metastasis activity in the experimental B16 melanoma lung metastasis model. The molecular mechanism underlying this effect is identified as inhibition of tumour-dependent RIPK1-induced programmed necrosis (necroptosis) of vascular endothelial cells, which facilitates tumour cell extravasation and metastasis. Compound 22b is a type II kinase inhibitor that interacts with the inactive conformation (DFG-out) of the RIPK1 kinase domain.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 1
Rotatable bonds 7
Topological polar surface area 86.27
Molecular weight 481.17
XLogP 5.04
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CCn1cc(c2c1ncnc2N)c1ccc2c(c1)CCN2C(=O)Cc1cccc(c1)OC(F)(F)F
Isomeric SMILES CCn1cc(c2c1ncnc2N)c1ccc2c(c1)CCN2C(=O)Cc1cccc(c1)OC(F)(F)F
InChI InChI=1S/C25H22F3N5O2/c1-2-32-13-19(22-23(29)30-14-31-24(22)32)16-6-7-20-17(12-16)8-9-33(20)21(34)11-15-4-3-5-18(10-15)35-25(26,27)28/h3-7,10,12-14H,2,8-9,11H2,1H3,(H2,29,30,31)
InChI Key APPXQUDJLJXULP-UHFFFAOYSA-N
Bioactivity Comments
In a selectivity screen several off-target kinases were identified, including FLT4, TrkA, TrkB, TrkC, Axl, EIF2AK1 (HRI), Mer, DDR1 and MAP4K5, whose IC50 determinations were all <40 nM [1]. However, 22b is >1500-fold selective for RIPK1 compared to the other subfamily members RIPK2, RIPK3, and RIPK4.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
receptor interacting serine/threonine kinase 1 Hs Inhibitor Inhibition 8.4 pKd - 1
⤷ pKd 8.4 (Kd 4.4x10-9 M) [1]
Description: Binding affinity value.
receptor interacting serine/threonine kinase 3 Hs Inhibitor Inhibition 5.1 pKd - 1
⤷ pKd 5.1 (Kd 7.2x10-6 M) [1]
receptor interacting serine/threonine kinase 1 Hs Inhibitor Inhibition 8.0 pIC50 - 1
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [1]
Description: Inhibition of RIPK1 enzymatic activity in vitro determined using Eurofins' KinaseProfiler assay.
eukaryotic translation initiation factor 2 alpha kinase 1 Hs Inhibitor Inhibition 7.6 pIC50 - 1
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [1]
mitogen-activated protein kinase kinase kinase kinase 5 Hs Inhibitor Inhibition 7.4 pIC50 - 1
⤷ pIC50 7.4 (IC50 3.7x10-8 M) [1]
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
neurotrophic receptor tyrosine kinase 3 Hs Inhibitor Inhibition 8.1 pIC50 - 1
⤷ pIC50 8.1 (IC50 7x10-9 M) [1]
neurotrophic receptor tyrosine kinase 2 Hs Inhibitor Inhibition 8.1 pIC50 - 1
⤷ pIC50 8.1 (IC50 8x10-9 M) [1]
fms related receptor tyrosine kinase 4 Hs Inhibitor Inhibition 7.7 pIC50 - 1
⤷ pIC50 7.7 (IC50 2x10-8 M) [1]
neurotrophic receptor tyrosine kinase 1 Hs Inhibitor Inhibition 7.6 pIC50 - 1
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [1]
MER proto-oncogene, tyrosine kinase Hs Inhibitor Inhibition 7.5 pIC50 - 1
⤷ pIC50 7.5 (IC50 2.9x10-8 M) [1]
pIC50 7.5 (IC50 2.9x10-8 M) [1]
AXL receptor tyrosine kinase Hs Inhibitor Inhibition 7.5 pIC50 - 1
⤷ pIC50 7.5 (IC50 3.5x10-8 M) [1]
discoidin domain receptor tyrosine kinase 1 Hs Inhibitor Inhibition 7.5 pIC50 - 1
⤷ pIC50 7.5 (IC50 3.5x10-8 M) [1]