TAZEMETOSTAT

Details

Stereochemistry	ACHIRAL
Molecular Formula	C34H44N4O4
Molecular Weight	572.7376
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCN(C1CCOCC1)C2=C(C)C(=CC(=C2)C3=CC=C(CN4CCOCC4)C=C3)C(=O)NCC5=C(C)C=C(C)NC5=O

InChI

InChIKey=NSQSAUGJQHDYNO-UHFFFAOYSA-N

InChI=1S/C34H44N4O4/c1-5-38(29-10-14-41-15-11-29)32-20-28(27-8-6-26(7-9-27)22-37-12-16-42-17-13-37)19-30(25(32)4)33(39)35-21-31-23(2)18-24(3)36-34(31)40/h6-9,18-20,29H,5,10-17,21-22H2,1-4H3,(H,35,39)(H,36,40)

HIDE SMILES / InChI

Molecular Formula	C34H44N4O4
Molecular Weight	572.7376
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Tazemetostat (EPZ-6438) is a selective inhibitor of histone-lysine N-methyltransferase EZH2. The drug is under clinical development (phase II) for the treatment of Diffuse Large B Cell Lymphoma, Malignant Mesothelioma and Synovial Sarcoma.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Histone-lysine N-methyltransferase EZH2 10	Inhibitor 8,456		2.5 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Malignant mesothelioma 6	Primary	Phase II 1,145	Unknown
Synovial sarcoma 7	Primary	Phase II 1,145	Unknown
Diffuse large B-cell lymphoma 22	Primary	Phase II 1,145	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
818 ng/mL	800 mg 2 times / day steady-state, oral		TAZEMETOSTAT plasma	Homo sapiens
829 ng/mL	800 mg 2 times / day steady-state, oral		TAZEMETOSTAT plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
4630 ng × h/mL	800 mg 2 times / day steady-state, oral		TAZEMETOSTAT plasma	Homo sapiens
3340 ng × h/mL	800 mg 2 times / day steady-state, oral		TAZEMETOSTAT plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.1 h	800 mg 2 times / day steady-state, oral		TAZEMETOSTAT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
12%	800 mg 2 times / day steady-state, oral		TAZEMETOSTAT plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
100 mg 2 times / day steady, oral Studied dose	unhealthy, 38 - 70 years	DLT: Neutropenia, Thrombocytopenia...
1600 mg 2 times / day multiple, oral Highest studied dose	unhealthy, adult	DLT: Thrombocytopenia...
1600 mg 2 times / day single, oral Highest studied dose	unhealthy, adult	DLT: Thrombocytopenia...
800 mg 2 times / day multiple, oral Recommended	unhealthy, adult	Disc. AE: Mood disorder NOS... Other AEs: Pain, Fatigue...
800 mg 2 times / day multiple, oral Recommended	unhealthy, adult	Other AEs: Decreased hemoglobin, Lymphocyte count decreased...

Showing 1 to 5 of 6 entries

Previous1 2Next

AEs

Show entries

AE	Significance	Dose	Population
Cardiotoxicity	grade 2 DLT	100 mg 2 times / day steady, oral Studied dose	unhealthy, 38 - 70 years
Diarrhoea	grade 3 DLT	100 mg 2 times / day steady, oral Studied dose	unhealthy, 38 - 70 years
Fatigue	grade 3 DLT	100 mg 2 times / day steady, oral Studied dose	unhealthy, 38 - 70 years
Nausea	grade 3 DLT	100 mg 2 times / day steady, oral Studied dose	unhealthy, 38 - 70 years
Vomiting	grade 3 DLT	100 mg 2 times / day steady, oral Studied dose	unhealthy, 38 - 70 years

Showing 1 to 5 of 64 entries

Previous1 2 3 4 5…13Next

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,929 inhibitor 2,238	inhibitor 2,416 inducer 429	inhibitor 2,486	inhibitor 2,195

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 1,041 CYP2C19 2,042 CYP1A2 2,139 CYP2B6 918 MATE1 409 MATE2 265 P-gp 1,725 BCRP 899 OATP1B1 1,068 OATP1B3 952 OCT1 613 OCT2 770 OAT1 717 OAT3 740 BSEP 546	CYP3A 219 P-gp 2,035 BCRP 687 OCT2 430 OAT3 385 MATE1 180 OATP1B1 497 OATP1B3 430	CYP3A 141 CYP1A2 819 CYP2B6 657 CYP2C8 190 CYP2C19 323

Drug as perpetrator

Show entries

Target	Modality	Activity	Metabolite
BCRP 974	inhibitor 4,001	no [IC50 >10 uM]
BCRP 974	inhibitor 4,001	no [IC50 >10 uM]	EPZ-6930 5
BSEP 550	inhibitor 4,001	no [IC50 >10 uM]
BSEP 550	inhibitor 4,001	no [IC50 >10 uM]	EPZ-6930 5
OAT1 722	inhibitor 4,001	no [IC50 >10 uM]

Showing 1 to 5 of 56 entries

Previous1 2 3 4 5…12Next

Drug as victim

Show entries

Target	Modality	Activity	Clinical evidence
CYP3A4 1,929	substrate 3,987	major
CYP3A 219	substrate 3,987	major	yes (co-administration study)
BCRP 687	substrate 3,987	no
MATE1 180	substrate 3,987	no
OAT3 385	substrate 3,987	no

Showing 1 to 5 of 9 entries

Previous1 2Next

Tox targets

Show entries

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,240	inhibitor 2,215

Showing 1 to 1 of 1 entries

Previous1Next

Sourcing

Sourcing

Show entries

Vendor/Aggregator	ID	URL
abcr GmbH	AB479418	http://www.abcr.com/shop/en/AB479418
AbMole Bioscience	M2677	http://www.abmole.com/products/epz-6438.html
Achemtek	0102-012746	http://www.achemtek.com/1403254-99-8
Acorn PharmaTech	ACN-029397	http://www.acornpharmatech.com/
Active Biopharma	ABP001111	http://www.activebiopharma.com/1403254-99-8

Showing 1 to 5 of 36 entries

Previous1 2 3 4 5…8Next

PubMed

Show entries

Title	Date	PubMed
		252160839
Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.	2013 May 7	23620515

Showing 1 to 2 of 2 entries

Previous1Next

Patents

Sample Use Guides

In Vivo Use Guide

Malignant Mesothelioma, Synovial Sarcoma: patients receive 800 mg of oral tazemetostat two times daily. Diffuse Large B Cell Lymphoma: patients receive 200, 400, 600 or 800 mg of the drug twice a day in combination with rituximab (IV, 375 mg/m2, day 1),pPrednisolone (PO, 40 mg/m2 in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m2, day 1), cyclophosphamide (IV, 750 mg/m2, day 1), vincristine (IV, 1.4 mg/m2, day 1): 8 cycles, every 21 days.

Route of Administration: Oral

In Vitro Use Guide

Treatment of WSU-DLCL2 with 1uM tazemetostat for 4 days resulted in a concentration-dependent reduction in global H3K27Me3 levels with an IC50 value of 9 nmol/L. Treatment of WSU-DLCL2 cells with 200 nM tazemetostat; KARPAS-422 with 100 nM; SU-DHL-6 with 200 nM; and Pfeiffer with 0.5 nM inhibited cell proliferation with IC50 values of 0.0086, 0.0018, 0.0047 and 0.00049 uM, respectively.

Substance Class	Chemical
Record UNII	Q40W93WPE1
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

EPZ-6438

Preferred Name

English

TAZEMETOSTAT

Official Name

English

EPZ6438

Code

English

TAZEMETOSTAT [USAN]

Common Name

English

E-7438

Code

English

Showing 1 to 5 of 11 entries

Previous1 2 3Next

Show entries

Classification Tree

Code System

Code

Designated

FDA ORPHAN DRUG

637118

Designated/Approved

FDA ORPHAN DRUG

607017

Designated

FDA ORPHAN DRUG

508415

Pharmacologic Substance

NCI_THESAURUS

C274

Positive

EU-Orphan Drug

EU/3/18/2004

Showing 1 to 5 of 7 entries

Previous1 2Next

Show entries

Code System

Code

Type

Description

EVMPD

SUB178719

PRIMARY

DRUG BANK

DB12887

PRIMARY

FDA UNII

Q40W93WPE1

PRIMARY

EPA CompTox

DTXSID201025831

PRIMARY

PUBCHEM

66558664

PRIMARY

Showing 1 to 5 of 15 entries

Previous1 2 3Next

Show entries

Related Record

Type

Details


					J2234208AE

HISTONE-LYSINE N-METHYLTRANSFERASE EZH2

TARGET -> INHIBITOR

Comments:

biochemical assay

Qualification:

IC50

Amount:

4 NANOMOLAR (average)


					6P89T5M073

TAZEMETOSTAT HYDROBROMIDE

SALT/SOLVATE -> PARENT

Amount:


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Comments:

In vitro, tazemetostat is 87.7 to 91.1% bound to human plasma proteins over the concentration range of 1 to 30 ?M.

Interaction Type:

BINDING

Amount:

[87.7 to 91.1] % (average)


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> SUBSTRATE

Amount:


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR

Amount:

Showing 1 to 5 of 6 entries

Previous1 2Next

Show entries

Related Record

Type

Details


					02473RPZ50

N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-4-METHYL-4'-(4-MORPHOLINYLMETHYL)-5-((TETRAHYDRO-2H-PYRAN-4-YL)AMINO)(1,1'-BIPHENYL)-3-CARBOXAMIDE

METABOLITE INACTIVE -> PARENT

Interaction Type:

MAJOR

Amount:


					OL9I57NLO8

3-AMINO-N-((4,6-DIMETHYL-2-OXO-1H-PYRIDIN-3-YL)METHYL)-2-METHYL-5-(4-(MORPHOLINOMETHYL)PHENYL)BENZAMIDE

METABOLITE -> PARENT

Amount:


					ON8SNW2Y82

N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-5-(ETHYLAMINO)-4-METHYL-4'-(4-MORPHOLINYLMETHYL)(1,1'-BIPHENYL)-3-CARBOXAMIDE

METABOLITE -> PARENT

Amount:

Showing 1 to 3 of 3 entries

Previous1Next

Show entries

Related Record

Type

Details


					Q40W93WPE1

TAZEMETOSTAT

ACTIVE MOIETY

Amount:

Showing 1 to 1 of 1 entries

Previous1Next

Name	Property Type	Amount	Parameters
Biological Half-life	PHARMACOKINETIC	3.1 hours (average)

blood-to-plasma ratio	PHARMACOKINETIC	0.73 (average)

Volume of Distribution	PHARMACOKINETIC	1230 LITERS (average)

Tmax	PHARMACOKINETIC	[1.05 to 2.17] hours (average)	SINGLE ORAL DOSE ADMINISTRATION 800 mg (average)

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator