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Details

Stereochemistry ABSOLUTE
Molecular Formula C21H22F2N6O2
Molecular Weight 428.4352
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LAROTRECTINIB

SMILES

O[C@H]1CCN(C1)C(=O)NC2=C3N=C(C=CN3N=C2)N4CCC[C@@H]4C5=CC(F)=CC=C5F

InChI

InChIKey=NYNZQNWKBKUAII-KBXCAEBGSA-N
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

HIDE SMILES / InChI

Molecular Formula C21H22F2N6O2
Molecular Weight 428.4352
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Larotrectinib (previously known as ARRY-470 and LOXO-101) is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Larotrectinib is in phase II clinical trials for the treatment patients with solid tumors, non-Hodgkin lymphoma and for the pediatric patients with advanced solid or primary CNS tumors.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.
2013 Nov
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101.
2015 Oct
Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence.
2017 Jun
Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion.
2018 Jun

Sample Use Guides

In Vivo Use Guide
Oral capsule of LOXO-101 (ARRY-470 (FREE BASE)) - 100mg BID
Route of Administration: Oral
In Vitro Use Guide
ARRY-470 is a selective kinase inhibitor with nanomolar activity against TRKA/B/C but no other significant kinase inhibition below 1000nM. Treatment of cells expressing MPRIP- or CD74-NTRK1 with ARRY-470, CEP-701 and, to a lesser extent, crizotinib, inhibited autophosphorylation of RIP-TRKA and CD74-TRKA. It induces cell-cycle arrest in G1 and apoptosis of KM12 cells.
Substance Class Chemical
Created
by admin
on Mon Oct 21 19:56:07 UTC 2019
Edited
by admin
on Mon Oct 21 19:56:07 UTC 2019
Record UNII
PF9462I9HX
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LAROTRECTINIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
BAY-2757556
Code English
LOXO-101
Code English
ARRY-470
Code English
LAROTRECTINIB [USAN]
Common Name English
LAROTRECTINIB [WHO-DD]
Common Name English
1-PYRROLIDINECARBOXAMIDE, N-(5-((2R)-2-(2,5-DIFLUOROPHENYL)-1-PYRROLIDINYL)PYRAZOLO(1,5-A)PYRIMIDIN-3-YL)-3-HYDROXY-, (3S)-
Systematic Name English
LAROTRECTINIB [INN]
Common Name English
(3S)-N-(5-((2R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN- 1-YL)PYRAZOLO(1,5-A)PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE- 1-CARBOXAMIDE
Systematic Name English
BAY2757556
Code English
Classification Tree Code System Code
NCI_THESAURUS C129825
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
NCI_THESAURUS C1967
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
EU-Orphan Drug EU/3/18/2098
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
FDA ORPHAN DRUG 578317
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
Code System Code Type Description
CAS
1223403-58-4
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY
MANUFACTURER PRODUCT INFORMATION
LOXO-101
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY MedKoo CAT NO: 206207CAS NO: 1223403-58-4Description: LOXO-101, also known as ARRY-470, is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models. The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. (Last updated: 6/9/2016).
NCI_THESAURUS
C115977
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY
ChEMBL
CHEMBL3545075
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY
PUBCHEM
46188928
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY
MANUFACTURER PRODUCT INFORMATION
ARRY 470
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY Biological Activity: LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models. The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Translocations involving the TRK kinase domain, mutations involving the TRK ligand-binding site, amplifications of NTRK, TRK splice variants, and autocrine/paracrine signaling are described in diverse tumor types, and may contribute to tumorigenesis. LOXO-101 is currently being developed by Loxo Oncology, Inc.
INN
10360
Created by admin on Mon Oct 21 19:56:07 UTC 2019 , Edited by admin on Mon Oct 21 19:56:07 UTC 2019
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> INDUCER
TARGET -> INHIBITOR
Active against NTRK gene fusions. Competitive to ATP binding site.
COMPETITIVE INHIBITOR
IC50
TRANSPORTER -> SUBSTRATE
In overexpressing BCRP and P-gp cell line, the estimate Km for both transporters is >300 ?M.
TRANSPORTER -> SUBSTRATE
In overexpressing BCRP and P-gp cell line, the estimate Km for both transporters is >300 ?M. Coadministration of larotrectinib with a single dose of a P-gp inhibitor (rifampin), increased the AUCinf of larotrectinib by 1.7-fold and the Cmax by 1.8-fold as compared to larotrectinib administered alone.
EXCRETED UNCHANGED
Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine
FECAL; URINE
METABOLIC ENZYME -> SUBSTRATE
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
IC50
BINDER->LIGAND
METABOLIC ENZYME -> INHIBITOR
Coadministration of multiple doses of larotrectinib with a sensitive CYP3A4 substrate (midazolam) increased the AUCinf and Cmax of midazolam by 1.7-fold as compared to midazolam administered alone.
TARGET -> INHIBITOR
IC50
Related Record Type Details
ACTIVE MOIETY
LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in preclinical models. LOXO-101 is an orally bioavailable, potent, ATP-competitive inhibitor of TRKA, TRKB, and TRKC. LOXO-101 has IC50 values in the low nanomolar range for inhibition of all three TRK family members in binding and cellular assays, with 100x selectivity over other kinases, and has shown acceptable pharmaceutical properties and safety in nonclinical models.
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC ORAL

DOSE

Volume of Distribution PHARMACOKINETIC DOSE

Tmax PHARMACOKINETIC BID