zidesamtinib   Click here for help

GtoPdb Ligand ID: 12392

Synonyms: Example 5 [US383715659] | NVL-520 | NVL520
Compound class: Synthetic organic
Comment: This is the chemical structure for the INN zidesamtinib (a tyrosine kinase inhibitor that is intended as an antineoplastic agent). Zidesamtinib's structure matches that for the brain penetrant ROS1 inhibitor NVL-520, that was designed to overcome ROS1G2032R-mediated resistance to lorlatinib, entrectinib and crizotinib [1]. Objective tumour responses have been observed in 3 patients with ROS1 fusion-positive lung cancers (including with brain metastases) that were resistant to other tyrosine kinase inhibitor therapies [1]. Turning Point Therapeutics' repotrectinib has also shown promise against ROS1G2032R, but NVL-520 is proposed as a more suitable rival in terms of CNS adverse events.
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 8
Hydrogen bond donors 1
Rotatable bonds 1
Topological polar surface area 91.17
Molecular weight 419.46
XLogP 2.19
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 CCN1C2=C(CC3=NN(C)N=C3C4=CC=C(C=C4[C@@H](C)OC5=CC2=CN=C5N)F)C=N1
Isomeric SMILES CCN1N=CC2=C1C3=CC(O[C@H](C)C4=CC(F)=CC=C4C5=NN(C)N=C5C2)=C(N)N=C3
InChI InChI=1S/C22H22FN7O/c1-4-30-21-13(11-26-30)7-18-20(28-29(3)27-18)16-6-5-15(23)9-17(16)12(2)31-19-8-14(21)10-25-22(19)24/h5-6,8-12H,4,7H2,1-3H3,(H2,24,25)/t12-/m1/s1
InChI Key DTWUUAFTYSMNQX-GFCCVEGCSA-N
Bioactivity Comments
In vitro, zidesamtinib (NVL-520) is active against diverse ROS1 fusions and resistance mutations, and proves more potent against the ROS1G2032R mutation than existing tyrosine kinase inhibitors crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib [1]. Zidesamtinib is more selective for ROS1 than these older inhibitors, with reduced NTRK inhibitory activity.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
c-ros oncogene 1, receptor tyrosine kinase Hs Inhibitor Inhibition >7.3 pKi - 2
⤷ pKi >7.3 (Ki <5x10-8 M) [2]
Description: Inhibition of ROS1G2032R
neurotrophic receptor tyrosine kinase 1 Hs Inhibitor Inhibition 6.3 – 7.3 pKi - 2
⤷ pKi 6.3 – 7.3 (Ki 5x10-7 – 5x10-8 M) [2]
Description: Inhibitin of WT TRKA
c-ros oncogene 1, receptor tyrosine kinase Hs Inhibitor Inhibition 9.1 pIC50 - 1
⤷ pIC50 9.1 (IC50 7x10-10 M) [1]
Description: Inhibition of wild-type ROS1 in an enzyme activity assay