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Details

Stereochemistry ABSOLUTE
Molecular Formula C25H25Cl2FN6O3
Molecular Weight 547.409
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of X-376

SMILES

C[C@@H](OC1=CC(=NN=C1N)C(=O)NC2=CC=C(C=C2)C(=O)N3CCN(C)CC3)C4=C(Cl)C=CC(F)=C4Cl

InChI

InChIKey=ONPGOSVDVDPBCY-CQSZACIVSA-N
InChI=1S/C25H25Cl2FN6O3/c1-14(21-17(26)7-8-18(28)22(21)27)37-20-13-19(31-32-23(20)29)24(35)30-16-5-3-15(4-6-16)25(36)34-11-9-33(2)10-12-34/h3-8,13-14H,9-12H2,1-2H3,(H2,29,32)(H,30,35)/t14-/m1/s1

HIDE SMILES / InChI

Molecular Formula C25H25Cl2FN6O3
Molecular Weight 547.409
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

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

Curator's Comment: Preclinical data demonstrated that X-396 penetrates the blood-brain barrier in mice.

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
212 ng/mL
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
X-396 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
311 ng/mL
225 mg 1 times / day multiple, oral
dose: 225 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
X-396 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
318 ng/mL
225 mg 1 times / day multiple, oral
dose: 225 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
X-396 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
3827 ng × h/mL
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
X-396 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
5330 ng × h/mL
225 mg 1 times / day multiple, oral
dose: 225 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
X-396 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
5530 ng × h/mL
225 mg 1 times / day multiple, oral
dose: 225 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
X-396 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
18.3 h
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
X-396 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
37.7 h
225 mg 1 times / day multiple, oral
dose: 225 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
X-396 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
33.2 h
225 mg 1 times / day multiple, oral
dose: 225 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
X-396 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
8.45%
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
X-396 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
likely [IC50 >50 uM]
moderate [IC50 14.6 uM]
moderate [IC50 19.1 uM]
moderate [IC50 20.6 uM]
no
no
no
no
no
no
no
no
no
yes [IC50 1.12 uM]
yes [IC50 3.69 uM]
yes [IC50 4.93 uM]
yes [IC50 9.13 uM]
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
majo
yes
PubMed

PubMed

TitleDatePubMed
Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.
2011 Jul 15
Patents

Sample Use Guides

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
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
Created
by admin
on Sat Dec 16 08:06:28 GMT 2023
Edited
by admin
on Sat Dec 16 08:06:28 GMT 2023
Record UNII
7DR7JMB8BH
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
X-376
Common Name English
(R)-6-AMINO-5-(1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)-N-(4-(4-METHYLPIPERAZINE-1-CARBONYL)PHENYL)PYRIDAZINE-3-CARBOXAMIDE
Systematic Name English
3-PYRIDAZINECARBOXAMIDE, 6-AMINO-5-((1R)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)-N-(4-((4-METHYL-1-PIPERAZINYL)CARBONYL)PHENYL)-
Systematic Name English
Code System Code Type Description
CAS
1365267-27-1
Created by admin on Sat Dec 16 08:06:29 GMT 2023 , Edited by admin on Sat Dec 16 08:06:29 GMT 2023
PRIMARY
PUBCHEM
56960447
Created by admin on Sat Dec 16 08:06:29 GMT 2023 , Edited by admin on Sat Dec 16 08:06:29 GMT 2023
PRIMARY
ChEMBL
CHEMBL3544934
Created by admin on Sat Dec 16 08:06:29 GMT 2023 , Edited by admin on Sat Dec 16 08:06:29 GMT 2023
PRIMARY
FDA UNII
7DR7JMB8BH
Created by admin on Sat Dec 16 08:06:29 GMT 2023 , Edited by admin on Sat Dec 16 08:06:29 GMT 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
INHIBITOR
IC50
TARGET -> INHIBITOR
INHIBITOR
IC50
Related Record Type Details
ACTIVE MOIETY