TASURGRATINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C32H37N5O6
Molecular Weight	587.6661
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CNC(=O)N1C=CC2=CC(OC3=CC=NC(NC(=O)C4=CC=C(C=C4)C5CCN(CCO)CC5)=C3)=C(OCCOC)C=C12

InChI

InChIKey=IBHOLSBDZMIPPT-UHFFFAOYSA-N

InChI=1S/C32H37N5O6/c1-33-32(40)37-14-10-25-19-29(28(21-27(25)37)42-18-17-41-2)43-26-7-11-34-30(20-26)35-31(39)24-5-3-22(4-6-24)23-8-12-36(13-9-23)15-16-38/h3-7,10-11,14,19-21,23,38H,8-9,12-13,15-18H2,1-2H3,(H,33,40)(H,34,35,39)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27535969

E-7090 is a novel selective inhibitor of fibroblast growth factor receptors, that displays potent anti-tumor activity. It is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. E-7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses E-7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E-7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E-7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E-7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. It is being investigated in a Phase I clinical trial for treatment of patients with solid tumors.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Fibroblast growth factor receptor 1 45 Target ID: P11362\|\|\|Q14307\|\|\|Q9UDF2 Gene ID: 2260.0 Gene Symbol: FGFR1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/27535969	Inhibitor 8297	0.7 nM [IC50]
Fibroblast growth factor receptor 2 25 Target ID: P21802\|\|\|Q14301\|\|\|Q1KHY5\|\|\|Q9NZU3\|\|\|Q9UIH8 Gene ID: 2263.0 Gene Symbol: FGFR2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/27535969	Inhibitor 8297	0.5 nM [IC50]
Fibroblast growth factor receptor 3 32 Target ID: P22607 Gene ID: 2261.0 Gene Symbol: FGFR3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/27535969	Inhibitor 8297	1.2 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Lung squamous cell carcinoma 2 Sources: https://clinicaltrials.gov/show/NCT02275910 https://www.ncbi.nlm.nih.gov/pubmed/27535969	Primary		Phase I 428	Unknown Approved Use Unknown
Breast cancer 434 Sources: https://clinicaltrials.gov/ct2/show/record/NCT02275910 https://www.ncbi.nlm.nih.gov/pubmed/27535969	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
337 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
372 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	140 mg 1 times / day multiple, oral dose: 140 mg route of administration: Oral experiment type: MULTIPLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
154 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
227 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
3860 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	140 mg 1 times / day multiple, oral dose: 140 mg route of administration: Oral experiment type: MULTIPLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2610 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4050 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:	E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
24 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:		E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
27 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31797489	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:		E-7090 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
180 mg 1 times / day multiple, oral Highest studied dose Dose: 180 mg, 1 times / day Route: oral Route: multiple Dose: 180 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574	DLT: ALT increased, AST increased... Dose limiting toxicities: ALT increased (grade 3, 33.3%) AST increased (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574

AEs

AE	Significance	Dose	Population
ALT increased	grade 3, 33.3% DLT	180 mg 1 times / day multiple, oral Highest studied dose Dose: 180 mg, 1 times / day Route: oral Route: multiple Dose: 180 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574
AST increased	grade 3, 33.3% DLT	180 mg 1 times / day multiple, oral Highest studied dose Dose: 180 mg, 1 times / day Route: oral Route: multiple Dose: 180 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/31797489 Page: p.574

Sourcing

Vendor/Aggregator	ID	URL
Excenen	EX-A2908	http://www.excenen.com/searchresultlist.php?id=EX-A2908
MuseChem	I006574	https://www.musechem.com/product/I006574.html

PubMed

Title	Date	PubMed
E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models.	2016 Nov	27535969

Patents

Sample Use Guides

In Vivo Use Guide

E-7090 starting dose 1 mg once a day with dose escalation in Cycle 1 in patients with solid tumors. Cycle 0 is for 7 days. For Cycle 1 and onward, each cycle is 28 days long. Subjects can continue treatment unless they meet discontinuation criteria.

Route of Administration: Oral

In Vitro Use Guide

E-7090 was tested on a panel of 39 human cancer cell lines in cell proliferation assays. The IC50 values observed ranged from 2 nM to greater than 10,000 nM. Thirteen cell lines were highly sensitive to E-7090, with IC50 values less than 100 nM. SNU-16 (human gastric cancer cell line) cells were treated with the indicated concentrations of E-7090 succinate in RPMI1640 containing 10% FBS for 4 hours and lysed with RIPA buffer containing protease and phosphatase inhibitors. E7090 succinate inhibited SNU-16 cell proliferation with an IC50 value of 5.7 nM.

Name

Type

Language

TASURGRATINIB

Official Name

English

FGF/FGFR PATHWAY INHIBITOR E7090

Common Name

English

E7090

Code

English

1H-INDOLE-1-CARBOXAMIDE, 5-((2-((4-(1-(2-HYDROXYETHYL)-4-PIPERIDINYL)BENZOYL)AMINO)-4-PYRIDINYL)OXY)-6-(2-METHOXYETHOXY)-N-METHYL-

Systematic Name

English

1-(2-HYDROXYETHYL)-7-(2-METHOXYETHOXY)-N-METHYL-3- OXO-7H-6-OXA-4-AZA-7(5)-INDOLA-5(2,4)-PYRIDINA-1(4)-PIPERIDINA-2(1,4)-BENZENAHEPTAPHANE-7-CARBOXAMIDE

Systematic Name

English

5-((2-(((4-(1-(2-HYDROXYETHYL)PIPERIDIN-4-YL)PHENYL)CARBONYL)AMINO)PYRIDIN-4-YL)OXY)-6-(2-METHOXYETHOXY)-N-METHYL-1H-INDOLE-1-CARBOXAMIDE

Common Name

English

E 7090 [WHO-DD]

Common Name

English

tasurgratinib [INN]

Common Name

English

E-7090

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C1967