TESEVATINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H25Cl2FN4O2
Molecular Weight	491.385
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12C[C@H](COC3=CC4=NC=NC(NC5=C(F)C(Cl)=C(Cl)C=C5)=C4C=C3OC)C[C@]1([H])CN(C)C2

InChI

InChIKey=HVXKQKFEHMGHSL-QKDCVEJESA-N

InChI=1S/C24H25Cl2FN4O2/c1-31-9-14-5-13(6-15(14)10-31)11-33-21-8-19-16(7-20(21)32-2)24(29-12-28-19)30-18-4-3-17(25)22(26)23(18)27/h3-4,7-8,12-15H,5-6,9-11H2,1-2H3,(H,28,29,30)/t13-,14-,15+

HIDE SMILES / InChI

Molecular Formula	C24H25Cl2FN4O2
Molecular Weight	491.385
Charge	0
Count

Stereochemistry	EPIMERIC
Additional Stereochemistry	No
Defined Stereocenters	2 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://adisinsight.springer.com/drugs/800020855
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17575237

Tesevatinib (EXEL-7647 or XL647) was optimized as an inhibitor of a spectrum of growth-promoting and angiogenic receptor tyrosine kinases (RTKs) to simultaneously block tumor growth and vascularization. In particular, Tesevatinib potently inhibits the EGF/ErbB2, VEGF, and ephrin RTK families. The drug is being developed by Kadmon Corporation under licence from Symphony Evolution (Symphony Capital Partners). Kadmon is developing tesevatinib for the treatment of autosomal polycystic kidney disease and solid cancers.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Epidermal growth factor receptor erbB1 58 Target ID: CHEMBL203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	0.3 nM [IC50]
Ephrin type-B receptor 4 5 Target ID: CHEMBL5147 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	1.4 nM [IC50]
Vascular endothelial growth factor receptor 2 104 Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	1.5 nM [IC50]
Epidermal growth factor receptor erbB1 58 Target ID: CHEMBL203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	0.3 nM [IC50]
Receptor protein-tyrosine kinase erbB-2 35 Target ID: CHEMBL1824 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	16.0 nM [IC50]
Vascular endothelial growth factor receptor 2 104 Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	1.5 nM [IC50]
Vascular endothelial growth factor receptor 3 41 Target ID: CHEMBL1955 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	8.7 nM [IC50]
Ephrin type-B receptor 4 5 Target ID: CHEMBL5147 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575237	Inhibitor 8297	1.4 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: http://adisinsight.springer.com/drugs/800020855	Primary	Phase III 656	Unknown Approved Use Unknown
Glioblastoma 65 Sources: http://adisinsight.springer.com/drugs/800020855	Primary	Phase III 656	Unknown Approved Use Unknown
Autosomal dominant polycystic kidney disease 7 Sources: http://adisinsight.springer.com/drugs/800020855	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
0.666 ng/mL/(mg dose) EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	4.68 mg/kg single, oral dose: 4.68 mg/kg route of administration: Oral experiment type: SINGLE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.28 ng/mL/(mg dose) EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	4.68 mg/kg 1 times / day steady-state, oral dose: 4.68 mg/kg route of administration: Oral experiment type: STEADY-STATE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.72 ng/mL/(mg dose) EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	300 mg 1 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
0.611 ng/mL/(mg dose) EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
10 ng × h/mL/kg EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	4.68 mg/kg single, oral dose: 4.68 mg/kg route of administration: Oral experiment type: SINGLE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
24.6 ng × h/mL/kg EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	4.68 mg/kg 1 times / day steady-state, oral dose: 4.68 mg/kg route of administration: Oral experiment type: STEADY-STATE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
34.1 ng × h/mL/kg EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	300 mg 1 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
9.6 ng × h/mL/kg EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
55.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	4.68 mg/kg single, oral dose: 4.68 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
64.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30030583	4.68 mg/kg 1 times / day steady-state, oral dose: 4.68 mg/kg route of administration: Oral experiment type: STEADY-STATE co-administered:		TESEVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
350 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 350 mg, 1 times / day Route: oral Route: multiple Dose: 350 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/	unhealthy n = 5 Health Status: unhealthy Condition: advanced solid malignancies Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/	DLT: QTc prolongation... Dose limiting toxicities: QTc prolongation (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/
350 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 350 mg, 1 times / day Route: oral Route: multiple Dose: 350 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22722787/	unhealthy n = 41 Health Status: unhealthy Condition: NSCLC Sex: M+F Food Status: UNKNOWN Population Size: 41 Sources: https://pubmed.ncbi.nlm.nih.gov/22722787/	Disc. AE: astrointestinal bleed, pneumonia... Other AEs: Pruritus, Dry skin... AEs leading to discontinuation/dose reduction: astrointestinal bleed (grade 3, 1 pt) pneumonia (grade 3, 1 pt) QTc prolongation (grade 3, 1 pt) onychomadesis (grade 2, 1 pt) Other AEs: Pruritus (grade 2, 5%) Dry skin (grade 2, 2%) Dysgeusia (grade 2, 2%) Mucosal inflammation (grade 2, 2%) Vomiting (grade 2, 2%) Diarrhea (grade 3, 5%) fatigue (grade 3, 2%) Sources: https://pubmed.ncbi.nlm.nih.gov/22722787/
300 mg 1 times / day multiple, oral (total daily dose) MTD Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/	unhealthy n = 6 Health Status: unhealthy Condition: advanced solid malignancies Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/	DLT: pneumonitis... Dose limiting toxicities: pneumonitis (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/
300 mg 1 times / day multiple, oral Studied dose Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22722787/	unhealthy n = 14 Health Status: unhealthy Condition: NSCLC Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/22722787/	Disc. AE: QTc prolongation, diarrhea... Other AEs: Nausea, Fatigue... AEs leading to discontinuation/dose reduction: QTc prolongation (grade 3, 1 pt) diarrhea (grade 3, 1 pt) rash (grade 3, 1 pt) gastrointestinal discomfort (grade 1, 1 pt) gastrointestinal bleed (grade 3, 1 pt) Blood creatinine increased (grade 2, 1 pt) Hyperkalemia (grade 2, 1 pt) Other AEs: Nausea (grade 2, 7%) Fatigue (grade 2, 14%) Anorexia (grade 2, 7%) Sources: https://pubmed.ncbi.nlm.nih.gov/22722787/
7 mg/kg 1 times / day multiple, oral (unknown) Studied dose Dose: 7 mg/kg, 1 times / day Route: oral Route: multiple Dose: 7 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/	unhealthy n = 2 Health Status: unhealthy Condition: advanced solid malignancies Sex: unknown Food Status: FASTED Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/	DLT: diarrhea... Dose limiting toxicities: diarrhea (grade 4, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/30030583/

AEs

PubMed

Title	Date	PubMed
Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647.	2007 Jun 15	17575237
EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation.	2008 Apr 15	18413839
New strategies to overcome limitations of reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer.	2010 Jul	20092908
EGFR-mutant lung adenocarcinomas treated first-line with the novel EGFR inhibitor, XL647, can subsequently retain moderate sensitivity to erlotinib.	2012 Feb	22173702
XL647--a multitargeted tyrosine kinase inhibitor: results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib.	2012 Jan	22011666
Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer.	2012 May	22722787

Patents

Sample Use Guides

In Vivo Use Guide

Two dosing schedules were evaluated; in the "intermittent 5 & 9 dosing" cohort, Tesevatinib (XL647) 350 mg for 5 days every 14 days was given; and in the "daily dosing" cohort, XL647 300 mg daily for 28 days was administered. XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with non-small-cell lung cancer.

Route of Administration: Oral

In Vitro Use Guide

In A431 cells, which express WT EGFR, Tesevatinib reduced cell viability with IC50 values of 13 nmol/L, with 95% confidence intervals of 10 to 15.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 02:09:33 GMT 2023` Edited by `admin` on `Sat Dec 16 02:09:33 GMT 2023`
Record UNII	F6XM2TN5A1
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

TESEVATINIB

Official Name

English

XL-647

Common Name

English

XL647

Code

English

EXEL-7647

Code

English

KD019

Code

English

4-QUINAZOLINAMINE, N-(3,4-DICHLORO-2-FLUOROPHENYL)-6-METHOXY-7-(((3A.ALPHA.,5.BETA.,6A.ALPHA.)-OCTAHYDRO-2-METHYLCYCLOPENTA(C)PYRROL-5-YL)METHOXY)-

Common Name

English

KD-019

Code

English

Tesevatinib [WHO-DD]

Common Name

English

TESEVATINIB [USAN]

Common Name

English

KD-020

Code

English

N-(3,4-DICHLORO-2-FLUOROPHENYL)-6-METHOXY-7-(((3AR,6AS)-2-METHYLOCTAHYDROCYCLOPENTA(C)PYRROL-5-YL)METHOXY)QUINAZOLIN-4-AMINE

Common Name

English

tesevatinib [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1967