GSK-2816126

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C31H38N6O2
Molecular Weight	526.6724
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC[C@H](C)N1C=C(C)C2=C1C=C(C=C2C(=O)NCC3=C(C)C=C(C)NC3=O)C4=CC=C(N=C4)N5CCNCC5

InChI

InChIKey=FKSFKBQGSFSOSM-QFIPXVFZSA-N

InChI=1S/C31H38N6O2/c1-6-22(5)37-18-20(3)29-25(30(38)34-17-26-19(2)13-21(4)35-31(26)39)14-24(15-27(29)37)23-7-8-28(33-16-23)36-11-9-32-10-12-36/h7-8,13-16,18,22,32H,6,9-12,17H2,1-5H3,(H,34,38)(H,35,39)/t22-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C31H38N6O2
Molecular Weight	526.6724
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. EZH2 inactivation by GSK126 is also effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126 in patients with MM may be warranted. GSK126 is undergoing phase I trials for hypermethylation-related cancers. GSK126 is in phase I diffuse large B cell lymphoma and follicular lymphoma. GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Histone-lysine N-methyltransferase EZH2 10	Inhibitor 8,504		9.9 nM [IC50]
Vascular endothelial growth factor A 3	Inhibitor 8,504

Conditions

Condition	Modality	Highest Phase	Product
Diffuse large B-cell lymphoma 22	Primary	Phase I 438	Unknown
Follicular lymphoma 4	Primary	Phase I 438	Unknown
Multiple myeloma 159	Primary	Phase I 438	Unknown
Solid tumors 147	Primary	Phase I 438	Unknown

C_max

Value	Dose	Analyte	Population
0.42 μg/mL	50 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
0.5 μg/mL	50 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
1.1 μg/mL	100 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
1 μg/mL	100 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
1.4 μg/mL	200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
1.5 μg/mL	200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
4 μg/mL	400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
3.5 μg/mL	400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
7.31 μg/mL	800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
7.46 μg/mL	800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
10.9 μg/mL	1200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
11.6 μg/mL	1200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
13 μg/mL	1800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
14.2 μg/mL	1800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
22.3 μg/mL	2400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
21.6 μg/mL	2400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
23.8 μg/mL	3000 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
30.5 μg/mL	3000 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
1.33 μg × h/mL	50 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
3.9 μg × h/mL	50 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
7 μg × h/mL	100 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
13.2 μg × h/mL	400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
14.8 μg × h/mL	400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
26.4 μg × h/mL	800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
33.3 μg × h/mL	800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
60.9 μg × h/mL	1200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
60.2 μg × h/mL	1200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
51.2 μg × h/mL	1800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
81.7 μg × h/mL	1800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
102 μg × h/mL	2400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
123 μg × h/mL	2400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
103 μg × h/mL	3000 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
183 μg × h/mL	3000 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
7.62 h	50 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
46.5 h	50 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
36.8 h	100 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
49.1 h	400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
39.7 h	400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
26.5 h	800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
27.35 h	800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
14.1 h	1200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
27.3 h	1200 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
31.8 h	1800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
29.88 h	1800 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
33.7 h	2400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
22.75 h	2400 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
22.5 h	3000 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens
27.25 h	3000 mg 2 times / week multiple, intravenous	GSK-2816126 plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
3000 mg 2 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT	DLT: Aspartate aminotransferase increase, ALT increased...
2400 mg 2 times / week multiple, intravenous MTD	unhealthy, ADULT

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AEs

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AE	Significance	Dose	Population
ALT increased	grade 2-3, 28.6% DLT	3000 mg 2 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT
Aspartate aminotransferase increase	grade 4, 14.3% DLT	3000 mg 2 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT

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PubMed

Show entries

Title	Date	PubMed
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.	2012 Dec 6	23051747
The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A.	2016 Apr	26898301
Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells.	2017 Jan 10	27926488

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Patents

Sample Use Guides

In Vivo Use Guide

Subject will be administered with a 50 milligram (mg) starting dose of GSK126 intravenous infusion over 2 - 4 hours, initially twice-weekly 3 weeks on / 1 week off in each 28-day cycle. Dose escalation will continue until an RP2D is determined or until an maximum tolerated dose (MTD) or a dose of 3000 mg twice-weekly is reached.

Route of Administration: Intravenous

In Vitro Use Guide

GSK126 showed significant effect on prostate cancer PC-3 and DU145 cell growth and apoptosis when the dose was higher than 50 umol/L.

Substance Class	Chemical
Record UNII	W4OGW9QZ97
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

GSK-126

Preferred Name

English

GSK-2816126

Common Name

English

GSK-2816126A

Code

English

1H-INDOLE-4-CARBOXAMIDE, N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-3-METHYL-1-((1S)-1-METHYLPROPYL)-6-(6-(1-PIPERAZINYL)-3-PYRIDINYL)-

Systematic Name

English

GSK 2816126 [WHO-DD]

Common Name

English

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Code System

Code

Type

Description

FDA UNII

W4OGW9QZ97

PRIMARY

EPA CompTox

DTXSID301025739

PRIMARY

SMS_ID

300000042352

PRIMARY

PUBCHEM

68210102

PRIMARY

CAS

1346574-57-9

PRIMARY

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Related Record

Type

Details


					J2234208AE

HISTONE-LYSINE N-METHYLTRANSFERASE EZH2

TARGET -> INHIBITOR

Comments:

The maximal dose and schedule attained with GSK2816126 has shown insufficient evidence of clinical activity, and does not justify further clinical investigation.

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Related Record

Type

Details


					W4OGW9QZ97

GSK-2816126

ACTIVE MOIETY

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

PubMed

Patents

Sample Use Guides

C_max

T_1/2