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
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
| 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 |
DescriptionCurator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB06097 | https://www.ncbi.nlm.nih.gov/pubmed/26320186
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
Cmax
| Value | Dose | Co-administered | 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 | Co-administered | 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 |
T1/2
| Value | Dose | Co-administered | 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 |
|---|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| yes [IC50 0.9522 uM] | ||||
| yes [IC50 10.684 uM] | ||||
| yes [IC50 26.3506 uM] | ||||
| yes [IC50 5.3547 uM] |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| yes |
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
| Substance Class |
Chemical
Created
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072702W9QD
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GSK-923295A
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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. | ||
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ALLOSTERIC
Ki
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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)
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