GSK-923295A

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C32H38ClN5O4
Molecular Weight	592.128
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)OC1=C(Cl)C=C(C=C1)C(=O)N[C@H](CNC(=O)CN(C)C)CC2=CC=C(C=C2)C3=CN4C=CC=C([C@H](C)O)C4=N3

InChI

InChIKey=WHMXDBPHBVLYRC-OFVILXPXSA-N

InChI=1S/C32H38ClN5O4/c1-20(2)42-29-13-12-24(16-27(29)33)32(41)35-25(17-34-30(40)19-37(4)5)15-22-8-10-23(11-9-22)28-18-38-14-6-7-26(21(3)39)31(38)36-28/h6-14,16,18,20-21,25,39H,15,17,19H2,1-5H3,(H,34,40)(H,35,41)/t21-,25-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20167803
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB06097 | https://www.ncbi.nlm.nih.gov/pubmed/26320186

GSK-923295 is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E), and the third novel drug candidate to arise from Cytokinetics' broad strategic alliance with GlaxoSmithKline (GSK). GSK-923295 demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors. GSK-923295 is the first drug candidate to enter human clinical trials that specifically targets CENP-E and is currently in Phase I human clinical trials being conducted by GSK. GSK-923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Centromere-associated protein E 1 Target ID: CHEMBL5870 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20167803	Inhibitor 8297		3.2 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 592 Sources: http://adisinsight.springer.com/drugs/800026868 https://clinicaltrials.gov/ct2/show/NCT00504790	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
7340 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	140 mg/m² 1 times / week multiple, intravenous dose: 140 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7120 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	190 mg/m² 1 times / week multiple, intravenous dose: 190 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8240 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	250 mg/m² 1 times / week multiple, intravenous dose: 250 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2020 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	40 mg/m² 1 times / week multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2230 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	80 mg/m² 1 times / week multiple, intravenous dose: 80 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
305 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	10 mg/m² 1 times / week multiple, intravenous dose: 10 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
14600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	140 mg/m² 1 times / week multiple, intravenous dose: 140 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
14700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	190 mg/m² 1 times / week multiple, intravenous dose: 190 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
19600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	250 mg/m² 1 times / week multiple, intravenous dose: 250 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4110 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	40 mg/m² 1 times / week multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
4700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	80 mg/m² 1 times / week multiple, intravenous dose: 80 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
541 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	10 mg/m² 1 times / week multiple, intravenous dose: 10 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
10.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	140 mg/m² 1 times / week multiple, intravenous dose: 140 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.16 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	190 mg/m² 1 times / week multiple, intravenous dose: 190 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	250 mg/m² 1 times / week multiple, intravenous dose: 250 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
10.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	40 mg/m² 1 times / week multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
9.23 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	80 mg/m² 1 times / week multiple, intravenous dose: 80 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6.04 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22020315/	10 mg/m² 1 times / week multiple, intravenous dose: 10 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	GSK-923295 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

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

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=440681337	yes [IC50 0.9522 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=440681337	yes [IC50 10.684 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174007425	yes [IC50 26.3506 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=440681337	yes [IC50 5.3547 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25725449/	yes

PubMed

Title	Date	PubMed
Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.	2010 Mar 30	20167803
First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer.	2012 Mar	22020315

Patents

Sample Use Guides

In Vivo Use Guide

Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK-923295 doses ranging from 10 to 250 mg/m(2). GSK-923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks.

Route of Administration: Intravenous

In Vitro Use Guide

Targeting CENPE with the small molecular inhibitor GSK-923295 showed inhibition of in vitro proliferation of 19 neuroblastoma cell lines (median IC(50), 41 nmol/L; range, 27-266 nmol/L)

Name

Type

Language

GSK-923295A

Code

English

GSK-923295

Code

English

BENZAMIDE, 3-CHLORO-N-((1S)-2-(((DIMETHYLAMINO)ACETYL)AMINO)-1-((4-(8-((1S)-1-HYDROXYETHYL)IMIDAZO(1,2-A)PYRIDIN-2-YL)PHENYL)METHYL)ETHYL)-4-(1-METHYLETHOXY)-

Systematic Name

English

GSK923295

Code

English

3-CHLORO-N-((1S)-1-(((2-(DIMETHYLAMINO)ACETYL)AMINO)METHYL)-2-(4-(8-((1S)-1-HYDROXYETHYL)IMIDAZO(1,2-A)PYRIDIN-2-YL)PHENYL)ETHYL)-4-ISOPROPOXY-BENZAMIDE

Systematic Name

English

GSK-295

Code

English

3-CHLORO-N-((1S)-2-((N,N-DIMETHYLGLYCYL)AMINO)-1-(4-(8-((1S)-1-HYDROXYETHYL)IMIDAZO(1,2-A)PYRIDIN-2-YL)BENZYL)ETHYL)-4-ISOPROPOXYBENZAMIDE

Systematic Name

English

Code System Code Type Description

FDA UNII

072702W9QD