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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 Tue Mar 06 11:02:27 UTC 2018
Edited
by admin
on Tue Mar 06 11:02:27 UTC 2018
Record UNII
PF9462I9HX
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LAROTRECTINIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name 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
Code System Code Type Description
CAS
1223403-58-4
Created by admin on Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
PRIMARY
MANUFACTURER PRODUCT INFORMATION
LOXO-101
Created by admin on Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
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 Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
PRIMARY
ChEMBL
CHEMBL3545075
Created by admin on Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
PRIMARY
PUBCHEM
46188928
Created by admin on Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
PRIMARY SWITZERF
MANUFACTURER PRODUCT INFORMATION
ARRY 470
Created by admin on Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
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 Tue Mar 06 11:02:27 UTC 2018 , Edited by admin on Tue Mar 06 11:02:27 UTC 2018
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
TARGET -> INHIBITOR
TARGET -> INHIBITOR
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.
ACTIVE MOIETY
Originator: Array BioPharma; Developer: Array BioPharma, Loxo Oncology; Class: Antineoplastic, Small molecule; Mechanism of Action: Tropomyosin-related kinase antagonist; Orphan Drug Status: Yes for Soft tissue sarcoma; New Molecular Entity: Yes; Highest Development Phases: Phase II for Solid tumours, Phase I for CNS cancer; Most Recent Events: 13 Jul 2016 LOXO 101 receives Breakthrough Therapy status for Solid tumours (Metastatic disease, Inoperable/Unresectable) in USA, 19 Apr 2016 Efficacy data from a phase I trial in CNS cancer released by Loxo Oncology, 17 Apr 2016 Interim efficacy and safety data from a phase I trial in Solid tumours presented at the Annual Meeting of American Association for Cancer Research (AACR-2016)
ACTIVE MOIETY
Drug: LOXO-101(Primary); Indications: Small cell lung cancer, Solid tumours; Focus: Adverse reactions, First in man, Therapeutic Use; Sponsor: Loxo Oncology; Most Recent Events: 17 Apr 2016 Results (n=43) presented at the 2016 American Association for Cancer Research (AACR) Annual Meeting , according to a Loxo Oncology media release., 17 Apr 2016 Results (n=43) published in a Loxo Oncology media release. 15 Mar 2016 Updated data from this trial will be presented at the 2016 American Association for Cancer Research (AACR) Annual Meeting, according to a Loxo Oncology media release