entrectinib   Click here for help

GtoPdb Ligand ID: 8290

Synonyms: NMS-E628 | Rozlytrek® | RXDX-101
Approved drug PDB Ligand
entrectinib is an approved drug (Japan and FDA (2019), EMA (2020))
Compound class: Synthetic organic
Comment: Entrectinib is an oral, brain penetrant, receptor tyrosine kinase (RTK) inhibitor that targets solid tumours that harbour activating alterations in NTRK1, NTRK2, NTRK3 (the Trk family RTKs), ROS1 or ALK [6]. NTRK1 fusion proteins are becoming recognised as oncogenic-drivers in NSCLC [3], so the ability of the compound to target these and ALK- and ROS1-rearrangements suggests it has the potential to become a useful oncology agent.
More recently entrectinib has been shown to inhibit NLRP3 inflammasome assembly and activation via a direct interaction with NIMA related kinase 7 (NEK7) that disrupts the NLRP3-NEK7 interaction [5]. This discovery suggests a role for entrectinib as an intervention for inflammasome-related diseases.
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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 3
Rotatable bonds 8
Topological polar surface area 85.52
Molecular weight 560.27
XLogP 6.13
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 CN1CCN(CC1)c1ccc(c(c1)NC1CCOCC1)C(=O)Nc1n[nH]c2c1cc(cc2)Cc1cc(F)cc(c1)F
Isomeric SMILES CN1CCN(CC1)c1ccc(c(c1)NC1CCOCC1)C(=O)Nc1n[nH]c2c1cc(cc2)Cc1cc(F)cc(c1)F
InChI InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)
InChI Key HAYYBYPASCDWEQ-UHFFFAOYSA-N
References
1. Al-Salama ZT, Keam SJ. (2019)
Entrectinib: First Global Approval.
Drugs, 79 (13): 1477-1483. [PMID:31372957]
2. Awad MM, Shaw AT. (2014)
ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
Clin Adv Hematol Oncol, 12 (7): 429-39. [PMID:25322323]
3. Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, Bauer TM, Liu SV, Ou SH, Jackman D et al.. (2015)
Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.
J Thorac Oncol, 10 (12): 1670-4. [PMID:26565381]
4. Fontana D, Ceccon M, Gambacorti-Passerini C, Mologni L. (2015)
Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK.
Cancer Med, 4 (7): 953-65. [PMID:25727400]
5. Jin X, Liu D, Zhou X, Luo X, Huang Q, Huang Y. (2023)
Entrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7.
Cell Rep Med, 4 (12): 101310. [PMID:38118409]
6. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L. (2015)
Entrectinib: a potent new TRK, ROS1, and ALK inhibitor.
Expert Opin Investig Drugs, 24 (11): 1493-500. [PMID:26457764]