compound 27 [PMID: 29775310]   Click here for help

GtoPdb Ligand ID: 9973

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 27 is a lead ERK1/2 inhibitor that was identified using biophysical fragment screening and structure-based optimization [1]. It was found to be potent, selective and orally bioavailable. Compound 27 inhibits both the catalytic kinase (phosphorylating) activity of ERK1/2, and the phosphorylation of ERK1/2. It is an alternative chemotype to SCH772984, but it retains the dual activity profile that was originally identified in SCH772984. Compound 27 has improved in vivo exposure compared to SCH772984.
(Note: ERK1= MAPK3, ERK2= MAPK1).
Click here for help

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.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

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.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

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.

✖
Hydrogen bond acceptors 9
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 116.68
Molecular weight 549.21
XLogP 3.58
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Click here for help

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.

✖
Canonical SMILES OCC(c1cccc(c1)C)NC(=O)C(N1Cc2c(C1=O)cc(cc2)c1nc(ncc1Cl)NC1CCOCC1)C
Isomeric SMILES OC[C@H](c1cccc(c1)C)NC(=O)[C@H](N1Cc2c(C1=O)cc(cc2)c1nc(ncc1Cl)NC1CCOCC1)C
InChI InChI=1S/C29H32ClN5O4/c1-17-4-3-5-19(12-17)25(16-36)33-27(37)18(2)35-15-21-7-6-20(13-23(21)28(35)38)26-24(30)14-31-29(34-26)32-22-8-10-39-11-9-22/h3-7,12-14,18,22,25,36H,8-11,15-16H2,1-2H3,(H,33,37)(H,31,32,34)/t18-,25-/m1/s1
InChI Key XHOJEECXVUMYMF-IQGLISFBSA-N
Bioactivity Comments
Compound 27 reduced both pRSK (a downstream phosphorylation target of ERK, the IC50 for this effect is 3.5 nM) and pERK1/2 levels (IC50 2.3 nM) in mutant BRAF cells in vitro and in vivo [1], the latter action indicating potential utility in tumours with acquired resistance to current BRAF inhibitors. It also suppressed pERK and pRSK levels in human colon carcinoma (Colo205) xenograft models and xenograft regression was observed after 15 days of treatment.
Off-targets (kinases inhibited by >50% at 100 nM): protein kinases D1 and D2 (PRKD1, PRKD2), and mitogen-activated protein kinase 15 (MAPK15/ERK7). Further off-targets that are inhibited by >50% at 1 μM compound 27 are listed in Supplementary Table 1 [1].
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 1 Hs Inhibitor Inhibition 8.5 pIC50 - 1
⤷ pIC50 8.5 (IC50 3x10-9 M) [1]