TESEVATINIB

Investigational

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

SMILES

COC1=C(OC[C@H]2C[C@H]3CN(C)C[C@H]3C2)C=C4N=CN=C(NC5=C(F)C(Cl)=C(Cl)C=C5)C4=C1

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

Description

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 62	Inhibitor 8,504	0.3 nM [IC50]
Receptor protein-tyrosine kinase erbB-2 35	Inhibitor 8,504	16.0 nM [IC50]
Vascular endothelial growth factor receptor 2 112	Inhibitor 8,504	1.5 nM [IC50]
Vascular endothelial growth factor receptor 3 41	Inhibitor 8,504	8.7 nM [IC50]
Ephrin type-B receptor 4 5	Inhibitor 8,504	1.4 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 211	Primary	Phase III 665	Unknown
Glioblastoma 66	Primary	Phase III 665	Unknown
Autosomal dominant polycystic kidney disease 7	Primary	Phase II 1,147	Unknown

C_max

Value	Dose	Analyte	Population
0.611 ng/mL/(mg dose)	300 mg single, oral	TESEVATINIB plasma	Homo sapiens
1.72 ng/mL/(mg dose)	300 mg 1 times / day steady-state, oral	TESEVATINIB plasma	Homo sapiens
0.666 ng/mL/(mg dose)	4.68 mg/kg single, oral	TESEVATINIB plasma	Homo sapiens
1.28 ng/mL/(mg dose)	4.68 mg/kg 1 times / day multiple, oral	TESEVATINIB plasma	Homo sapiens
233.1 ng/mL	350 mg single, oral	TESEVATINIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
9.6 ng × h/mL/kg	300 mg single, oral	TESEVATINIB plasma	Homo sapiens
34.1 ng × h/mL/kg	300 mg 1 times / day steady-state, oral	TESEVATINIB plasma	Homo sapiens
10 ng × h/mL/kg	4.68 mg/kg single, oral	TESEVATINIB plasma	Homo sapiens
24.6 ng × h/mL/kg	4.68 mg/kg 1 times / day multiple, oral	TESEVATINIB plasma	Homo sapiens
748 ng × h/mL	350 mg single, oral	TESEVATINIB plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
55.5 h	4.68 mg/kg single, oral	TESEVATINIB plasma	Homo sapiens
64.2 h	4.68 mg/kg 1 times / day multiple, oral	TESEVATINIB plasma	Homo sapiens
55.5 h	350 mg single, oral	TESEVATINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
5%			TESEVATINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
350 mg 1 times / day multiple, oral Highest studied dose	unhealthy	DLT: QTc prolongation...
350 mg 1 times / day multiple, oral Highest studied dose	unhealthy	Disc. AE: pneumonia, astrointestinal bleed... Other AEs: Diarrhea, fatigue...
300 mg 1 times / day multiple, oral MTD	unhealthy	DLT: pneumonitis...
300 mg 1 times / day multiple, oral Studied dose	unhealthy	Disc. AE: QTc prolongation, gastrointestinal discomfort... Other AEs: Nausea, Fatigue...
7 mg/kg 1 times / day multiple, oral Studied dose	unhealthy	DLT: diarrhea...

Showing 1 to 5 of 5 entries

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AEs

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AE	Significance	Dose	Population
QTc prolongation	grade 3, 2 patients DLT	350 mg 1 times / day multiple, oral Highest studied dose	unhealthy
onychomadesis	grade 2, 1 pt Disc. AE	350 mg 1 times / day multiple, oral Highest studied dose	unhealthy
Dry skin	grade 2, 2%	350 mg 1 times / day multiple, oral Highest studied dose	unhealthy
Dysgeusia	grade 2, 2%	350 mg 1 times / day multiple, oral Highest studied dose	unhealthy
Mucosal inflammation	grade 2, 2%	350 mg 1 times / day multiple, oral Highest studied dose	unhealthy

Showing 1 to 5 of 24 entries

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PubMed

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Title	Date	PubMed
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
Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer.	2012 May	22722787

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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.

Show entries

Name

Type

Language

TESEVATINIB

Official Name

English

tesevatinib [INN]

Preferred Name

English

XL-647

Common Name

English

XL647

Code

English

EXEL-7647

Code

English

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Classification Tree

Code System

Code

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Designated

FDA ORPHAN DRUG

802420

Antineoplastic Agent

NCI_THESAURUS

C1742

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Designated

FDA ORPHAN DRUG

506715

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Code System

Code

Type

Description

USAN

BC-18

PRIMARY

INN

10079

PRIMARY

WIKIPEDIA

Tesevatinib

PRIMARY

NCI_THESAURUS

C62496

PRIMARY

PUBCHEM

10458325

PRIMARY

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ACTIVE MOIETY


					F6XM2TN5A1

TESEVATINIB

SALT/SOLVATE (PARENT)


					GKB6T21I50

TESEVATINIB TOSYLATE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound