X-376

Investigational

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 Search

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

Description
Sources: http://xcovery.com/medical-professionals/#Ensartinib | http://oncologypro.esmo.org/Meeting-Resources/ELCC-2017/EXalt3-A-phase-III-study-of-ensartinib-X-396-in-anaplastic-lymphoma-kinase-ALK-positive-non-small-cell-lung-cancer-NSCLC

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 25 Target ID: CHEMBL4247 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21613408 \| http://xcovery.com/medical-professionals/#Ensartinib \| https://www.ncbi.nlm.nih.gov/pubmed/25322323	Inhibitor 8297		0.4 nM [IC50]
Hepatocyte growth factor receptor 54 Target ID: CHEMBL3717 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21613408 \| http://xcovery.com/medical-professionals/#Ensartinib \| https://www.ncbi.nlm.nih.gov/pubmed/25322323	Inhibitor 8297		0.74 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT02767804 http://adisinsight.springer.com/drugs/800036425	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
212 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33044566/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29563138/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29563138/	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

Value	Dose	Analyte	Population
3827 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33044566/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29563138/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29563138/	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

T_1/2

Value	Dose	Analyte	Population
18.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33044566/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29563138/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29563138/	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
8.45% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33044566/	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

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 BCRP 699 CYP2C19 1478 CYP2C8 911 CYP3A5 73 CYP1A2 1524 MRP1 106 P-gp 1461	CYP3A 191 P-gp 1537	CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Metabolite
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	likely [IC50 >50 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	moderate [IC50 14.6 uM]
CYP3A5 130	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	moderate [IC50 19.1 uM]
CYP2C8 965	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	moderate [IC50 20.6 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	no
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 1
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	no
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 1
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 1
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 1
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 1
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 1
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 1.12 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 3.69 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 4.93 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 9.13 uM]
CYP2B6 1001	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	yes	M465 1
CYP3A4 1925	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	yes	M465 1

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A 191	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	majo
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes

PubMed

Title	Date	PubMed
Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.	2011 Jul 15	21613408

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 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

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X-376

ACTIVE MOIETY

Details

SMILES

InChI

DescriptionSources: http://xcovery.com/medical-professionals/#Ensartinib | http://oncologypro.esmo.org/Meeting-Resources/ELCC-2017/EXalt3-A-phase-III-study-of-ensartinib-X-396-in-anaplastic-lymphoma-kinase-ALK-positive-non-small-cell-lung-cancer-NSCLC

CNS Activity

Originator

Approval Year

Targets

Conditions

Approved Use

Cmax

AUC

T1/2

Funbound

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

PubMed

Patents

Sample Use Guides

Description
Sources: http://xcovery.com/medical-professionals/#Ensartinib | http://oncologypro.esmo.org/Meeting-Resources/ELCC-2017/EXalt3-A-phase-III-study-of-ensartinib-X-396-in-anaplastic-lymphoma-kinase-ALK-positive-non-small-cell-lung-cancer-NSCLC

C_max

T_1/2

F_unbound

Drug as perpetrator