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=CC=C(CN4CCN(C)CC4)C=C23)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: https://www.ncbi.nlm.nih.gov/pubmed/19474163http://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 14 Target ID: CHEMBL3024 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19690138	Inhibitor 8297		0.5 nM [Ki]
Serine/threonine-protein kinase PLK1 14 Target ID: P53350 Gene ID: 5347.0 Gene Symbol: PLK1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/19690138	Inhibitor 8297		2.2 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Non-Hodgkin's lymphoma 79 Sources: http://adisinsight.springer.com/drugs/800026258	Primary	Phase I 428	Unknown Approved Use Unknown
Solid tumors 145 Sources: http://adisinsight.springer.com/drugs/800026258	Primary	Phase I 428	Unknown Approved Use Unknown
Non-Hodgkin's lymphoma 79 Sources: https://clinicaltrials.gov/ct2/show/NCT00536835	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
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
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
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
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
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
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

AUC

Value	Dose	Analyte	Population
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
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
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
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
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
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

T_1/2

Value	Dose	Analyte	Population
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
9.61 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
12.9 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
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
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
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

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461	BCRP 561 P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/25192198/	yes [IC50 9 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 561	substrate 3367 Sources: https://neoplasiaresearch.com/pms/index.php/jcru/article/view/558	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25192198/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/21459796/

PubMed

Title	Date	PubMed
The PLK1 inhibitor GSK461364A is effective in poorly differentiated and anaplastic thyroid carcinoma cells, independent of the nature of their driver mutations.	2013 Oct	23509868

Patents

Sample Use Guides

In Vivo Use Guide

Schedule 1 - GSK461364 given once weekly on Day 1, 8 and 15 every 28 days; Schedule 2 - GSK 461364 given twice weekly Days 1, 2, 8, 9, 15 and 16; Schedule 3 Daily on Day 1 to Day 15 every 21 days. in adult subjects with advanced solid tumor or Non-Hodgkins Lymphoma as a 4 hour infusion in either a final volume of 500 or 1000 mLs. The starting dose for Stage A - Schedule 1 was 50 mg and doses were to be escalated as described in protocol until maximum tolerated dose established.

Route of Administration: Intravenous

In Vitro Use Guide

In vitro, GSK461364A inhibited growth of brain metastatic variant (231-BR) of the MDA-MB-231 human breast cancer cell line with the IC50 of 5 nM, and after 24 hours more than 70% of cells treated with PLK1 accumulated in the G2–M phase of the cell cycle, compared with 16% in the vehicle-treated control group.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 08:35:37 GMT 2023` Edited by `admin` on `Sat Dec 16 08:35:37 GMT 2023`
Record UNII	8QO27TK6Q4
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

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

GSK-461364A

Code

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