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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 of GSK-923295A

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

Molecular Formula C32H38ClN5O4
Molecular Weight 592.128
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
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.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
3.2 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
7340 ng/mL
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
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
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
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
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
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

AUC

ValueDoseCo-administeredAnalytePopulation
14600 ng × h/mL
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
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
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
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
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
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
10.3 h
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
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
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
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
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
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

Overview

CYP3A4CYP2C9CYP2D6hERG



OverviewOther

Other InhibitorOther SubstrateOther Inducer


Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
PubMed

PubMed

TitleDatePubMed
Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
2010 Mar 30
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
Patents

Sample Use Guides

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
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)
Substance Class Chemical
Created
by admin
on Fri Dec 15 16:37:43 GMT 2023
Edited
by admin
on Fri Dec 15 16:37:43 GMT 2023
Record UNII
072702W9QD
Record Status Validated (UNII)
Record Version
  • Download
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
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY
NCI_THESAURUS
C91080
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY
SMS_ID
100000175314
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY
MANUFACTURER PRODUCT INFORMATION
GSK-923295A
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with Ki of 3.2 nM, and less potent to mutant I182 and T183. IC50 Value: 3.2 nM(Ki), Target: CENP-E,GSK923295 inhibits release of inorganic phosphate and stabilizes CENP-E motor domain interaction with microtubules, reduces the rate of ATP-promoted dissociation of CENP-E from MT (koff, MT) by more than 50-fold. GSK923295 causes failure of metaphase chromosome alignment and induces mitotic arrest. GSK923295 is a potent inhibitor of tumor cell growth, with an average GI50 of 253 nM and a median GI50 of 32 nM for 237 tumor cell lines. GSK923295 inhibits tumor cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signaling is also inhibited.
PUBCHEM
46898058
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY
CAS
1088965-37-0
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY
EPA CompTox
DTXSID50677145
Created by admin on Fri Dec 15 16:37:43 GMT 2023 , Edited by admin on Fri Dec 15 16:37:43 GMT 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
ALLOSTERIC
Ki
Related Record Type Details
ACTIVE MOIETY
Class: Antineoplastic, Small molecule; Mechanism of Action: Centromere protein E inhibitor, Mitosis inhibitor; Highest Development Phase: Suspended for Solid tumours; Most Recent Events: 19 Nov 2009 Drug interactions data from a preclinical trial in Cancer presented at the 21st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2009), 19 Nov 2009 Pharmacodynamics data from in vitro studies in Solid tumours presented at the 21st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2009), 01 Jun 2009 Pharmacodynamics data from a preclinical trial in Cancer presented at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO-2009)