ENSARTINIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C26H27Cl2FN6O3
Molecular Weight	561.435
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

C[C@@H](OC1=CC(=NN=C1N)C(=O)NC2=CC=C(C=C2)C(=O)N3C[C@H](C)N[C@H](C)C3)C4=C(Cl)C=CC(F)=C4Cl

InChI

InChIKey=GLYMPHUVMRFTFV-QLFBSQMISA-N

InChI=1S/C26H27Cl2FN6O3/c1-13-11-35(12-14(2)31-13)26(37)16-4-6-17(7-5-16)32-25(36)20-10-21(24(30)34-33-20)38-15(3)22-18(27)8-9-19(29)23(22)28/h4-10,13-15,31H,11-12H2,1-3H3,(H2,30,34)(H,32,36)/t13-,14+,15-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C26H27Cl2FN6O3
Molecular Weight	561.435
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

X-396 (Ensartinib) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Ensartinib is currently in a global phase 3 trial in ALK positive non-small cell lung cancer (NSCLC) patients. The phase 1/2 clinical findings support the preclinical results that the use of ensartinib may result in favorable therapeutic outcomes in patients with ALK NSCLC, including patients with CNS metastases. In this study, ensartinib was generally well tolerated with the most common adverse event being a rash.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ALK tyrosine kinase receptor 24	Inhibitor 8,504		0.4 nM [IC50]
Hepatocyte growth factor receptor 56	Inhibitor 8,504		0.74 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 211	Primary		Phase III 665	Unknown

C_max

Value	Dose	Analyte	Population
318 ng/mL	225 mg 1 times / day multiple, oral	X-396 plasma	Homo sapiens
311 ng/mL	225 mg 1 times / day multiple, oral	X-396 plasma	Homo sapiens
212 ng/mL	200 mg single, oral	X-396 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
5530 ng × h/mL	225 mg 1 times / day multiple, oral	X-396 plasma	Homo sapiens
5330 ng × h/mL	225 mg 1 times / day multiple, oral	X-396 plasma	Homo sapiens
3827 ng × h/mL	200 mg single, oral	X-396 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
33.2 h	225 mg 1 times / day multiple, oral	X-396 plasma	Homo sapiens
37.7 h	225 mg 1 times / day multiple, oral	X-396 plasma	Homo sapiens
18.3 h	200 mg single, oral	X-396 plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
8.45%	200 mg single, oral		X-396 plasma	Homo sapiens

Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 926 BCRP 910 CYP2C19 2,057 CYP2C8 1,057 CYP3A5 136 CYP1A2 2,153 MRP1 116 P-gp 1,741	P-gp 2,052 CYP3A 220	CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity
MRP1 232	inhibitor 4,027	likely [IC50 >50 uM]
CYP2C19 2,141	inhibitor 4,027	moderate [IC50 14.6 uM]
CYP3A5 201	inhibitor 4,027	moderate [IC50 19.1 uM]
CYP2C8 1,117	inhibitor 4,027	moderate [IC50 20.6 uM]
CYP1A2 2,333	inhibitor 4,027	no

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A 220	substrate 4,014	major
P-gp 2,052	substrate 4,014	yes

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

Eligible patients with ALK+ NSCLC will receive oral X-396 (ensartinib) at 225mg QD with or without food until progression or unacceptable toxicity develops

Route of Administration: Oral

In Vitro Use Guide

X-396 inhibited endogenous ALK phosphorylation and potential downstream signaling pathways in H3122 lung cancer cells harboring the EML4-ALK E13;A20 fusion at low concentrations of drug (100-1000 nM).

Substance Class	Chemical
Record UNII	SMA5ZS5B22
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

ENSARTINIB

Official Name

English

3-PYRIDAZINECARBOXAMIDE, 6-AMINO-5-((1R)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)-N-(4-(((3R,5S)-3,5-DIMETHYL-1-PIPERAZINYL)CARBONYL)PHENYL)

Preferred Name

English

ENSARTINIB [USAN]

Common Name

English

ensartinib [INN]

Common Name

English

X-396

Code

English

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Tyrosine Kinase Inhibitor

NCI_THESAURUS

C141136

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Code System

Code

Type

Description

SMS_ID

100000174627

PRIMARY

USAN

EF-132

PRIMARY

CAS

1370651-20-9

PRIMARY

PUBCHEM

56960363

PRIMARY

DRUG BANK

DB14860

PRIMARY

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SALT/SOLVATE -> PARENT

Amount:

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Related Record

Type

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					SMA5ZS5B22

ENSARTINIB

ACTIVE MOIETY

Amount:

Showing 1 to 1 of 1 entries

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator