Home Cytoskeletal Signaling Kinesin inhibitor - Apoptosis related activator GSK923295 For research use only.

GSK923295

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. GSK923295 induces post-mitotic apoptosis. Phase 1.

GSK923295 Chemical Structure

GSK923295 Chemical Structure

CAS No. 1088965-37-0

Purity & Quality Control

Batch: S709001 DMSO]100 mg/mL]false]Ethanol]100 mg/mL]false]Water]Insoluble]false Purity: 99.8%
99.8

GSK923295 Related Products

Signaling Pathway

Kinesin Signaling Pathways

Kinesin Signaling Pathway

Biological Activity

Description 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. GSK923295 induces post-mitotic apoptosis. Phase 1.
Features First potent, CENP-E-selective inhibitor that has been tested in Phase I clinical trials for treatment of Refractory Cancers.
Targets
CENP-E [1]
(Cell-free assay)
3.2 nM(Ki)
In vitro
In vitro

GSK923295 is the first potent and selective inhibitor of the mitotic kinesin centromere-associated protein-E (CENP-E). [1][2] GSK923295 is uncompetitive with both ATP and microtubules (MT), inhibiting CENP-E MT-stimulated ATPase activity with a Ki of 3.2 nM, highly selective over other kinesins. 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. [1] GSK923295 inhibits tumor cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signaling is also inhibited. [4]
Kinase Assay Enzymology
Kinesin motor domains are expressed in Escherichia coli BL21(DE3) and purified. CENP-E proteins includes residues 2–340 with a carboxyl-terminal 6-his tag. All studies using MT are conducted in PEM25 buffer [25mM PipesK+ (pH 6.8), 2mM MgCl2, 1mM EGTA] . The IC50 for steady-state inhibition is determined at 500 μM ATP, 5 μM MT, and 1 nM CENP-E in PEM25 buffer.
Cell Research Cell lines Tumor cell lines
Concentrations ~10 μM
Incubation Time 72 h
Method

Cell-growth inhibition assays are performed by MDS in 384-well plates, and DNA content of fixed cells stained with DAPI using an Incell 1000 is analyzed. DNA content is determined 24 h after seeding (T0) and after exposure to varying concentrations of drug for an additional 72 h (T72). All T72 measurements are normalized to T0. Curves are analyzed using the XLfit curve-fitting tool to determine the concentration of GSK923295 yielding 50% growth inhibition relative to T0 and Ymax values (GI50).
In Vivo
In vivo

GSK923295 produces clear increases in the abundance of mitotic figures and scattered apoptotic bodies in tumors. GSK923295 causes a dose-dependent increase in the ratio of 4n to 2n nuclei. GSK923295 exhibits robust, dose-dependent antitumor activity against Colo205 xenografts, including partial and complete regressions at the 125 mg/kg dose.[1] GSK923295 demonstrates significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts, may be a valuable therapeutic target in pediatric cancer. [3]
Animal Research Animal Models mice bearing xenografts of the Colo205 colon tumor-cell line
Dosages 125 mg/kg, two cycles of three daily injections separated by 1 week
Administration i.p.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00504790 Completed
Cancer
GlaxoSmithKline
 June 25 2007 Phase 1

Chemical Information & Solubility

Molecular Weight 592.13 Formula

C32H38ClN5O4
CAS No. 1088965-37-0 SDF Download GSK923295 SDF
Smiles CC(C)OC1=C(C=C(C=C1)C(=O)NC(CC2=CC=C(C=C2)C3=CN4C=CC=C(C4=N3)C(C)O)CNC(=O)CN(C)C)Cl
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 100 mg/mL ( (168.88 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble


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In vivo
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