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

Structure Search

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

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 24 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 8504		0.4 nM [IC50]
Hepatocyte growth factor receptor 56 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 8504		0.74 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 211 Sources: https://clinicaltrials.gov/ct2/show/NCT02767804 http://adisinsight.springer.com/drugs/800036425	Primary		Phase III 665	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
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
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
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

AUC

Value	Dose	Analyte	Population
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
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
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

T_1/2

Value	Dose	Analyte	Population
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
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
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

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 2252 inducer 1087	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 926 BCRP 910 CYP2C19 2057 CYP2C8 1057 CYP3A5 136 CYP1A2 2153 MRP1 116 P-gp 1741	P-gp 2052 CYP3A 220	CYP2B6 669

Drug as perpetrator

Target	Modality	Activity	Metabolite
MRP1 232	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	likely [IC50 >50 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	moderate [IC50 14.6 uM]
CYP3A5 201	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	moderate [IC50 19.1 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	moderate [IC50 20.6 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	no
CYP1A2 2333	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 3
CYP2B6 1160	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	no
CYP2B6 1160	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 3
CYP2C19 2141	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 3
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 3
CYP2D6 2546	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	no
CYP2D6 2546	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 3
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	no	M465 3
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 1.12 uM]
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 3.69 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 4.93 uM]
BCRP 985	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/32231067/	yes [IC50 9.13 uM]
CYP2B6 1160	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	yes	M465 3
CYP3A4 2633	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	yes	M465 3

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A 220	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/33044566/	major
P-gp 2052	substrate 4014 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).

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

6-AMINO-5-((1R)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)- N-(4-((3R,5S)-3,5-DIMETHYLPIPERAZINE- 1-CARBONYL)PHENYL)PYRIDAZINE-3-CARBOXAMIDE

Systematic Name

English

Ensartinib [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825