larotrectinib   Click here for help

GtoPdb Ligand ID: 8909

Synonyms: (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide [3] | example 14 [US8865698 B2] [3] | LOXO-101 | Vitrakvi®
Approved drug
larotrectinib is an approved drug (FDA (2018), EMA (2019))
Compound class: Synthetic organic
Comment: Larotrectinib (LOXO-101) is an orally available, potent and selective inhibitor of the receptor tyrosine kinases of the TRK family [2-3]. In these referenced patents, data is provided for inhibition of neurotrophic tyrosine kinase, receptor, type 1 (NTRK1, a.k.a. TrkA) .
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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 5
Topological polar surface area 86
Molecular weight 428.18
XLogP 3.07
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 OC1CCN(C1)C(=O)Nc1cnn2c1nc(cc2)N1CCCC1c1cc(F)ccc1F
Isomeric SMILES O[C@H]1CCN(C1)C(=O)Nc1cnn2c1nc(cc2)N1CCC[C@@H]1c1cc(F)ccc1F
InChI InChI=1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
InChI Key NYNZQNWKBKUAII-KBXCAEBGSA-N
No information available.
Summary of Clinical Use Click here for help
Larotrectinib (LOXO-101) was evaluated in clinical trial in patients with advanced solid tumours with NTRK fusions (NCT02576431). Larotrectinib showed a significant and durable anti-tumour effect in patients with NTRK fusion-positive cancers in Phase 2 trial [1]. Click here to link to ClinicalTrials.gov's full list of larotrectinib trials.
In June 2018, the FDA accepted a New Drug Application (NDA) for larotrectinib, and granted priority review. This led to accelerated approval in November 2018 [4]. Under this approval larotrectinib (Vitrakvi) can be used across a range of different tumour types (i.e. which have arisen from different tissues) so long as they harbour NTRK fusions. Suitable patients (adults and paediatric) will have tumours that are metastatic or are unsuitable for surgical resection, and for which there is no satisfactory alternative treatments. In the European Union, the EMA granted orphan drug designation for larotrectinib's use as a treatment for a number of rare cancers: 2016 (soft tissue sarcoma), 2018 (salivary gland cancer, glioma, papillary thyroid cancer). Full EMA approval was granted in September 2019.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Abberant activity of these proteins underlies growth signals that support the growth of tumours. Hyperactivity of TRKs can arise due to genetic abnormalites such as translocations in the TRK kinase domain, mutations in the TRK ligand-binding site, amplifications of NTRK or the expression of TRK splice variants. Inhibitors of these proteins would be expected to ameliorate the effects of abnormal activity.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02122913 A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer Phase 1 Interventional Bayer
NCT02576431 A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors Phase 2 Interventional Bayer