LAROTRECTINIB

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

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

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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

Targets

Primary Target	Pharmacology	Potency
Nerve growth factor receptor Trk-A 15	Inhibitor 8,504	20.0 nM [IC50]
Neurotrophic tyrosine kinase receptor type 2 14	Inhibitor 8,504	20.0 nM [IC50]
NT-3 growth factor receptor 9	Inhibitor 8,504	20.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 147	Primary	Approved 8,583	VITRAKVI
Central nervous system neoplasms 4	Primary	Phase II 1,147	Unknown
Non-Hodgkin's lymphoma 81	Primary	Phase II 1,147	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
788 ng/mL	100 mg 2 times / day steady-state, oral		LAROTRECTINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
4351 ng × h/mL	100 mg 2 times / day steady-state, oral		LAROTRECTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.9 h	100 mg single, oral		LAROTRECTINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years	Other AEs: Fatigue, Pyrexia...
100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years	Other AEs: ALT increased, AST increased...
100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years	Disc. AE: Brain edema, Intestinal perforation... Other AEs: Fatigue, Nausea...
150 mg 2 times / day steady, oral Higher than recommended	unhealthy, adult	DLT: Alanine aminotransferase increased, Aspartate aminotransferase increased...
200 mg 2 times / day steady, oral Highest studied dose	unhealthy, adult	DLT: Dizziness...

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AEs

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AE	Significance	Dose	Population
Nasal congestion	all grades, 10%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Decreased appetite	all grades, 11%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Back pain	all grades, 12%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Pain in extremity	all grades, 12%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Abdominal pain	all grades, 13%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1,087 inhibitor 2,252 substrate 1,946	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 BSEP 550 CYP1A2 2,153 CYP2B6 926 CYP2C19 2,057 CYP2C8 1,057 MATE1 415 MATE2 267 OAT1 725 OAT3 747 OATP1B1 1,079 OATP1B3 961 OCT1 620 OCT2 779 P-gp 1,741	BCRP 697 OAT1 395 OAT3 391 OATP1B1 503 OATP1B3 435 OCT1 393 OCT2 434 P-gp 2,052	CYP1A2 832 CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no
BSEP 554	inhibitor 4,027	no
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2B6 1,160	inducer 1,966	no

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Drug as victim

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Target	Modality	Activity
OAT1 395	substrate 4,014	no
OAT3 391	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no
OCT1 393	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA00171P	https://www.aablocks.com/goods/Goods/detail?id=AA00171P
Aaron Chemicals	AR0017TH	http://www.aaronchem.com/1223403-58-4
abcr GmbH	AB463081	http://www.abcr.com/shop/en/AB463081
AbMole Bioscience	M6151	http://www.abmole.com/products/loxo-101.html
Acorn PharmaTech	ACN-043424	http://www.acornpharmatech.com/

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PubMed

PubMed

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Title	Date	PubMed
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	29233640

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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.

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Name

Type

Language

larotrectinib [INN]

Preferred Name

English

LAROTRECTINIB

Official Name

English

BAY-2757556

Code

English

LOXO-101

Code

English

ARRY-470

Code

English

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Designated/Approved

FDA ORPHAN DRUG

578317

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Positive

EU-Orphan Drug

EU/3/18/2098

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Code System

Code

Type

Description

DRUG BANK

DB14723

PRIMARY

CAS

1223403-58-4

PRIMARY

MANUFACTURER PRODUCT INFORMATION

LOXO-101

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).

DRUG CENTRAL

5305

PRIMARY

EPA CompTox

DTXSID101020707

PRIMARY

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ACTIVE MOIETY