naporafenib   Click here for help

GtoPdb Ligand ID: 10658

Synonyms: compound 15 [PMID: 31059256] | example 1156 [WO2014151616A1] | LXH-254 | LXH254
PDB Ligand
Compound class: Synthetic organic
Comment: Naporafenib (LXH254) is an investigational, potent, selective and orally bioavailable RAF inhibitor that was designed to target RAS mutant cancers, i.e.those that harbour genetic alterations in the RAS-RAF-MEK-ERK (MAPK) pathway [2]. It is one of the compounds claimed in Novartis' patent WO2014151616A1 [1]. Naporafenib is a Type-2 kinase inhibitor that binds the DFG-out conformation of the kinase.
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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 7
Hydrogen bond donors 2
Rotatable bonds 9
Topological polar surface area 96.81
Molecular weight 502.18
XLogP 4.47
No. Lipinski's rules broken 0
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 OCCOc1cc(cc(n1)N1CCOCC1)c1cc(ccc1C)NC(=O)c1ccnc(c1)C(F)(F)F
Isomeric SMILES OCCOc1cc(cc(n1)N1CCOCC1)c1cc(ccc1C)NC(=O)c1ccnc(c1)C(F)(F)F
InChI InChI=1S/C25H25F3N4O4/c1-16-2-3-19(30-24(34)17-4-5-29-21(12-17)25(26,27)28)15-20(16)18-13-22(32-6-9-35-10-7-32)31-23(14-18)36-11-8-33/h2-5,12-15,33H,6-11H2,1H3,(H,30,34)
InChI Key UEPXBTCUIIGYCY-UHFFFAOYSA-N
Bioactivity Comments
LXH254 stabilises RAF dimerization (CRAF:BRAF dimers) in vitro, with an EC50 of 160 nM and effectively suppresses signaling [2]. Selectivity screening in the KINOMEscan® platform revealed that other than BRAF and CRAF, the only other kinases inhibited by more than 80% (at 1 μM) were PDGFRb (>99%), DDR1 (>99%) and DDR2 (>84%). This level of selectivity is an improvement in comparison to other Type 2 RAF inhibitors. In vivo anti-tumour efficacy of LXH254 has been demonstrated in the Calu-6 xenograft nude rat model.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
B-Raf proto-oncogene, serine/threonine kinase Hs Inhibitor Inhibition 8.9 pKd - 2
⤷ pKd 8.9 (Kd 1.3x10-9 M) [2]
Description: Binding affinity determined using the KinomeScan® platform.
Raf-1 proto-oncogene, serine/threonine kinase Hs Inhibitor Inhibition 8.4 pKd - 2
⤷ pKd 8.4 (Kd 3.6x10-9 M) [2]
Description: Binding affinity determined using the KinomeScan® platform.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
discoidin domain receptor tyrosine kinase 1 Hs Inhibitor Inhibition 8.7 pKd - 2
⤷ pKd 8.7 (Kd 1.8x10-9 M) [2]
Description: Binding affinity determined using the KinomeScan® platform.
discoidin domain receptor tyrosine kinase 2 Hs Inhibitor Inhibition 8.0 pKd - 2
⤷ pKd 8.0 (Kd 1x10-8 M) [2]
Description: Binding affinity determined using the KinomeScan® platform.
platelet derived growth factor receptor beta Hs Inhibitor Inhibition 7.8 pKd - 2
⤷ pKd 7.8 (Kd 1.4x10-8 M) [2]
Description: Binding affinity determined using the KinomeScan® platform.