GSK-461364

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C27H28F3N5O2S
Molecular Weight	543.604
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H](OC1=C(SC(=C1)N2C=NC3=C2C=C(CN4CCN(C)CC4)C=C3)C(N)=O)C5=CC=CC=C5C(F)(F)F

InChI

InChIKey=ZHJGWYRLJUCMRT-QGZVFWFLSA-N

InChI=1S/C27H28F3N5O2S/c1-17(19-5-3-4-6-20(19)27(28,29)30)37-23-14-24(38-25(23)26(31)36)35-16-32-21-8-7-18(13-22(21)35)15-34-11-9-33(2)10-12-34/h3-8,13-14,16-17H,9-12,15H2,1-2H3,(H2,31,36)/t17-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C27H28F3N5O2S
Molecular Weight	543.604
Charge	0
Count

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

Description
Sources: http://adisinsight.springer.com/drugs/800026258
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19690138

GSK-461364 is a potent, selective, reversible, ATP-competitive inhibitor of Plk1. GSK-461364 broadly inhibits cancer cell proliferation with differential survival outcome. GSK-461364 blocks cells in G2 and M phases of the cell cycle and causes M-phase caspase-3/caspase-7 activation. GSK-461364 is efficacious in xenograft tumor models. GlaxoSmithKline is developing GSK-461364 for the treatment of solid tumours and non-Hodgkin's lymphoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase PLK1 15 Target ID: CHEMBL3024 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19690138	Inhibitor 8504		0.5 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-Hodgkin's lymphoma 81 Sources: http://adisinsight.springer.com/drugs/800026258	Primary		Phase I 438	Unknown Approved Use Unknown
Solid tumors 147 Sources: http://adisinsight.springer.com/drugs/800026258	Primary		Phase I 438	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
411 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	225 mg 1 times / week multiple, intravenous dose: 225 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
139 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	100 mg 1 times / week multiple, intravenous dose: 100 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
61.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	50 mg 1 times / week multiple, intravenous dose: 50 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
149 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	150 mg 1 times / week multiple, intravenous dose: 150 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
120 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	75 mg 2 times / week multiple, intravenous dose: 75 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
456 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	300 mg 1 times / week multiple, intravenous dose: 300 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
2953 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	225 mg 1 times / week multiple, intravenous dose: 225 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1369 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	100 mg 1 times / week multiple, intravenous dose: 100 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
665 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	50 mg 1 times / week multiple, intravenous dose: 50 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1362 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	150 mg 1 times / week multiple, intravenous dose: 150 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
980 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	75 mg 2 times / week multiple, intravenous dose: 75 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3774 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	300 mg 1 times / week multiple, intravenous dose: 300 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
8.99 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	225 mg 1 times / week multiple, intravenous dose: 225 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	100 mg 1 times / week multiple, intravenous dose: 100 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
13.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	50 mg 1 times / week multiple, intravenous dose: 50 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9.61 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	150 mg 1 times / week multiple, intravenous dose: 150 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
12.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	75 mg 2 times / week multiple, intravenous dose: 75 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9.18 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21459796/	300 mg 1 times / week multiple, intravenous dose: 300 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-461364 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1741	BCRP 697 P-gp 2052

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/25192198/	yes [IC50 9 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 697	substrate 4014 Sources: https://neoplasiaresearch.com/pms/index.php/jcru/article/view/558	yes
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/25192198/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/21459796/

PubMed

Title	Date	PubMed
Comprehensive analysis of kinase inhibitor selectivity.	2011-10-30	22037378
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010-11-24	21095574
Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis.	2009-09-01	19690138

Patents

Sample Use Guides

In Vivo Use Guide

The final recommended phase II dose for GSK-461364 was 225 mg administered intravenously in schedule A (on days 1, 8, and 15 of 28-day cycles)

Route of Administration: Intravenous

In Vitro Use Guide

In a proliferation assay, GSK-461364 causes cell growth inhibition in a majority of the 74 tested cancer cell lines, 89% of cell lines responded to GSK-461364 with a gI50 (concentration required to inhibit 50% cell growth) of ≤ 100 nM

Substance Class	Chemical Created by `admin` on `Mon Mar 31 22:11:38 GMT 2025` Edited by `admin` on `Mon Mar 31 22:11:38 GMT 2025`
Record UNII	8QO27TK6Q4
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

GSK-461364A

Preferred Name

English

GSK-461364

Code

English

5-(6-((4-METHYLPIPERAZIN-1-YL)METHYL)-1H-BENZIMIDAZOL-1-YL)-3-(((1R)-1-(2-(TRIFLUOROMETHYL)PHENYL)ETHYL)OXY)THIOPHENE-2-CARBOXAMIDE

Systematic Name

English

2-THIOPHENECARBOXAMIDE, 5-(6-((4-METHYL-1-PIPERAZINYL)METHYL)-1H-BENZIMIDAZOL-1-YL)-3-((1R)-1-(2-(TRIFLUOROMETHYL)PHENYL)ETHOXY)-

Systematic Name

English

GSK461364

Code

English

GSK 461364 [WHO-DD]

Common Name

English

Code System Code Type Description

NCI_THESAURUS

C70948