GSK923295

Catalog No.S7090 Batch:S709001

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Technical Data

Formula

C32H38ClN5O4
Molecular Weight 592.13 CAS No. 1088965-37-0
Solubility (25°C)* In vitro DMSO 100 mg/mL (168.88 mM)
Ethanol 100 mg/mL (168.88 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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

Protocol (from reference)

Kinase Assay:[1]
  • 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] supplemented with 10 μM paclitaxel. The IC50 for steady-state inhibition is determined at 500 μM ATP, 5 μM MT, and 1 nM CENP-E in PEM25 buffer.
Cell Assay:[1]
  • 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).
Animal Study:[1]
  • 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.

Customer Product Validation

, , Nat Chem Biol, 2016, 12(4):226-32.

Selleck's GSK923295 has been cited by 32 publications

Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers [ Nat Cancer, 2024, 5(1):66-84] PubMed: 38151625
A conserved CENP-E region mediates BubR1-independent recruitment to the outer corona at mitotic onset [ Curr Biol, 2024, 34(5):1133-1141.e4] PubMed: 38354735
A farnesyl-dependent structural role for CENP-E in expansion of the fibrous corona [ J Cell Biol, 2024, 223(1)e202303007] PubMed: 37934467
Epigenetic dysregulation from chromosomal transit in micronuclei [ Nature, 2023, 619(7968):176-183] PubMed: 37286593
Epigenetic dysregulation from chromosomal transit in micronuclei [ Nature, 2023, 619(7968):176-183] PubMed: 37286593
Molecular landscape and functional characterization of centrosome amplification in ovarian cancer [ Nat Commun, 2023, 14(1):6505] PubMed: 37845213
ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE [ Cell Death Dis, 2023, 14(7):456] PubMed: 37479754
α-Tubulin detyrosination links the suppression of MCAK activity with taxol cytotoxicity [ J Cell Biol, 2023, 222(2)e202205092] PubMed: 36459065
Tetraploidy-linked sensitization to CENP-E inhibition in human cells [ Mol Oncol, 2023, 17(6):1148-1166] PubMed: 36688680
3D Ultrastructural Visualization of Mitosis Fidelity in Human Cells Using Serial Block Face Scanning Electron Microscopy (SBF-SEM) [ Bio Protoc, 2023, 13(13):e4708] PubMed: 37449034

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.