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Fig. 1 · Structure
Cat. No.
A11435
CAS No.
1088965-37-0
Formula
C32H38ClN5O4
Mol. Weight
592.13

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GSK-923295

Cat. No. A11435 CAS 1088965-37-0

CENP-E inhibitor

GSK-923295, is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E, (CENP-E).

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Publications for GSK-923295

1 publication citing this product

  1. Amber S Zhou, .et al. , PLoS Biol, 2023, Oct 26;21(10):e3002339 PMID: 37883329
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Biological Activity

Bioactivity / Mechanism

GSK923295 inhibits microtubule-stimulated CENP-E ATPase activity through an allosteric mechanism uncompetitive with ATP and microtubules. The reported human CENP-E Ki was 3.2 ± 0.2 nM (SD; n = 4). Biochemical experiments supported stabilization of a strongly microtubule-bound motor state and slowed inorganic-phosphate release. Murine CENP-E was less sensitive than the human enzyme. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target Activity Value
CENP-E Ki 3.2 nM

In Vitro Studies

In a 237-line human tumor-cell panel, 72-hour GSK923295 exposure gave a median GI50 of 32 nM and an average of 253 nM. Responses ranged from 12 nM to >10,000 nM; HT-3 and SNU-1 were among the least sensitive lines. These growth-inhibition endpoints do not establish uniform cytotoxicity. [1]

In Cal51 cells, 50 nM GSK923295 combined with 5 nM paclitaxel or 4 nM vinorelbine increased daughter-cell death after early focusing of multipolar spindles during 48–72-hour imaging. Adding GSK923295 did not detectably impair spindle focusing. These results concern the tested combinations and cellular context. [2]

CENP-E ATPase inhibition and microtubule-bound-state stabilization

Biochemical assay · Purified human, murine and canine CENP-E motor domains; human I182L/T183A mutant [1]

GSK923295 inhibited microtubule-stimulated ATPase uncompetitively with respect to ATP and microtubules. Copelleting and phosphate-release experiments supported stabilization of a strongly microtubule-bound motor state. Murine CENP-E was less sensitive than human CENP-E.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Microtubule-stimulated CENP-E ATPase inhibitionKi Human wt: 3.2 ± 0.2 nM; canine wt: 1.6 ± 0.1 nM; murine wt: 67 ± 5 nM; human I182L/T183A: 61 ± 8 nM[1]
CENP-E microtubule association and inorganic-phosphate releaseQualitative comparison Increased motor recovery in the microtubule pellet across tested nucleotide conditions; slowed phosphate release with inhibitor.[1]

Literature-Reported Treatment Conditions

Treatment concentration
Steady-state assay: 1 nM CENP-E, 5 μM microtubules and 500 μM ATP; inhibitor concentration varied. Copelleting: 3 μM motor, 6 μM microtubules, 1 mM indicated nucleotide and 20 μM inhibitor.
Method
ATPase concentration-response and kinetic analysis; SDS/PAGE analysis of supernatant/pellet fractions.
Co-treatment
Paclitaxel (10 μM) was a microtubule-stabilizing assay component, not a cellular combination-treatment experiment.
Reported limits
Vehicle and timing not established from the retrieved main text. Variable-substrate kinetic experiments are not represented as having the single fixed-substrate concentration-response conditions.
Methods and source locations

Compound reported in the paper: GSK923295

Evidence applies to the material named in this paper. No salt conversion or Adooq lot equivalence is inferred.

Results: biochemical characterization; Table 1 and footnote; Figure 1B-D and caption; Materials and Methods: Enzymology

Microtubule-stimulated CENP-E ATPase inhibition: Table 1 values are ± SD (n = 4). Steady-state ATPase concentration-response; estimates corrected for enzyme concentration. — Table 1, including footnote; Enzymology

CENP-E microtubule association and inorganic-phosphate release: Matched inhibitor-present/absent copelleting and presteady-state phosphate-release experiments. No rate estimated from curves. — Figure 1C-D image/caption; biochemical Results; Enzymology

Growth-inhibition response across 237 tumor cell lines

Cell-based study · Panel of 237 human tumor cell lines [1]

After 72-hour exposure, sensitivity varied by more than three orders of magnitude. Most lines were sensitive, but HT-3 and SNU-1 had GI50 values above 10,000 nM. The authors found no correlation between proliferation rate and GI50.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Growth inhibition relative to baseline and maximal growthGI50 Median: 32 nM; average: 253 nM; range: 12 nM to >10,000 nM; 212/237 lines <100 nM.[1]
Limited growth inhibition in HT-3 and SNU-1GI50 >10,000 nM for both HT-3 and SNU-1[1]

Literature-Reported Treatment Conditions

Treatment concentration
Varying concentrations of GSK923295; full dose series not established from retrieved main text.
Exposure duration
72 h continuous exposure, following baseline measurement 24 h after seeding.
Method
384-well DNA-content growth-inhibition assay; Incell 1000 and XLfit analysis.
Reported limits
Vehicle, replicate count and full concentration series not established from the retrieved main text; individual Dataset S1 values not retrieved.
Methods and source locations

Compound reported in the paper: GSK923295

Evidence applies to the material named in this paper. No salt conversion or Adooq lot equivalence is inferred.

Results: growth inhibition across 237 cell lines; Figure 4A image/caption; Materials and Methods: Cell Culture and Growth Inhibition

Growth inhibition relative to baseline and maximal growth: DAPI-stained fixed-cell DNA content at baseline and after 72-hour drug exposure; concentration-response fitting. GI50 is a growth endpoint, not a treatment dose or biochemical Ki. — Growth-inhibition Results; Figure 4A; Cell Culture and Growth Inhibition

Limited growth inhibition in HT-3 and SNU-1: Same 237-line panel; resistance determinant not identified by the authors. — Growth-inhibition Results immediately preceding Figure 4

Low-dose CENP-E inhibition in microtubule-poison-treated Cal51 cells

Cell-based study · Cal51 breast cancer cells with histone H2B-mScarlet and tubulin-eGFP reporters [2]

Adding 50 nM GSK923295 to low-dose paclitaxel or vinorelbine increased daughter-cell death among cells that focused multipolar spindles before anaphase. GSK923295 did not detectably impair spindle focusing in these conditions. Vinorelbine combinations also increased polar chromosome misalignment and overall daughter-cell death.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Daughter-cell death following early focusing of multipolar spindlesQualitative comparison Increased with GSK923295 plus paclitaxel or vinorelbine versus the respective microtubule poison alone.[2]
Spindle polarity during mitotic progressionQualitative comparison No detectable impairment of spindle focusing upon addition of GSK923295.[2]

Literature-Reported Treatment Conditions

Treatment concentration
GSK923295: 50 nM; paclitaxel: 5 nM; vinorelbine: 4 nM.
Exposure duration
48–72 h timelapse imaging; drugs added approximately 1 h before acquisition unless otherwise noted.
Method
Live-cell timelapse microscopy with classification of spindle polarity, polar chromosomes and daughter-cell fate.
Vehicle
DMSO; GSK923295 dissolved in DMSO. Final vehicle percentage not established.
Co-treatment
Paclitaxel or vinorelbine, tested separately with GSK923295; corresponding single-agent and vehicle controls.
Reported limits
No numerical synergy index adopted from unacquired S1 File Table C. Findings describe combination conditions, not single-agent therapeutic efficacy.
Methods and source locations

Compound reported in the paper: GSK923295; Compound label in the paper: CENP-Ei

Evidence applies to the material named in this paper. No salt conversion or Adooq lot equivalence is inferred.

Results: Loss of an additional 3 to 4 chromosomes confers sensitivity to microtubule poisons; Figure 6B-G; Methods: Cell culture, Microscopy, Statistical analysis; corrected S1 Data Figure 6B/C/F/G sheets

Daughter-cell death following early focusing of multipolar spindles: 48–72 h timelapse microscopy; Figure 6G reports unpaired t-test comparisons with p < 0.05 and mean ± SEM. Corrected workbook includes three replicate rows; cell count denominator not asserted. — Figure 6G image/caption and corresponding corrected S1 Data sheet

Spindle polarity during mitotic progression: Vehicle, inhibitor-alone, microtubule-poison-alone and combination conditions in Figure 6B-D; relevant comparisons labeled nonsignificant in B/C. — Figure 6B-D image/caption; corrected S1 Data Figure 6B/C sheets

In Vivo Studies

GSK923295A at 125 mg/kg intraperitoneally produced objective responses in 13 of 35 evaluable pediatric solid tumor xenograft models. Activity varied by model, with no neuroblastoma regressions. Excessive toxicity excluded all eight ALL xenograft models; treated-panel mortality was 64.4% in ALL-bearing mice versus 5.2% across solid tumor models. The results do not establish clinical efficacy or tolerability. [3]

Pediatric xenograft activity and host toxicity

Animal study · PPTP solid tumor xenografts in female CB17SC-F scid−/− mice (most solid models) or BALB/c nu/nu mice (glioma); ALL xenografts in female NOD/scid−/− mice [3]

GSK923295A produced objective responses in a subset of evaluable solid tumor models. Neuroblastoma models did not regress. Excessive toxicity rendered all eight ALL models and two solid tumor models inevaluable under the study exclusion rule.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Objective response and event-free-survival distributions in solid tumorsPanel response 13/35 evaluable solid models: 9 MCR, 3 CR, 1 PR; significant EFS difference versus controls in 32/35.[3]
Treatment-associated mortality and evaluabilityMortality ALL: 64.4% (n = 59); solid tumors: 5.2% (n = 367). All 8 ALL models and solid models KT-5 and Rh28 excluded for >25% mortality.[3]
Best objective response in neuroblastoma xenograftsResponse category No regressions; best response PD2, observed in 5 of 6 neuroblastoma models.[3]

Conditions shared by the study groups

Route
Intraperitoneal
Frequency
Daily on days 1–3 and 8–10
Vehicle
As reported: 1:1 dimethylacetamide/Cremophor EL mixture with 96% acidified water, pH 5.0 using HCl.
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
Solid tumor panel
125 mg/kg per daily dose		Contemporaneous control groups; 10 mice per group for solid tumors and 8 for ALL. Control dosing formulation not established from the retrieved main text.13/35 evaluable models had objective responses; 32/35 had significant EFS-distribution differences; mortality 5.2% (n = 367). KT-5 and Rh28 excluded for excessive toxicity.[3]
ALL panel toxicity
125 mg/kg per daily dose		Contemporaneous control groups; 10 mice per group for solid tumors and 8 for ALL. Control dosing formulation not established from the retrieved main text.Mortality 64.4% (n = 59); all eight ALL models inevaluable because of excessive toxicity.[3]
Solid tumor panel
Model: PPTP solid tumor xenografts in female SCID or nude mice
Treatment course: Days 1–3 and 8–10, repeated at day 21.
Reported limits: Supplied salt/form not established; supplementary per-animal table not retrieved.
ALL panel toxicity
Model: Eight ALL xenograft models in female NOD/SCID mice
Treatment course: Days 1–3 and 8–10 only; no day-21 repeat.
Reported limits: Supplied salt/form not established; supplementary per-animal table not retrieved.
Methods and source locations

Compound reported in the paper: GSK923295A

Evidence applies to the material named in this paper. No salt conversion or Adooq lot equivalence is inferred.

Materials and Methods: In Vivo Tumor Growth Inhibition Studies, Determination of Response, Overall Group Response, Statistical Methods, Drugs and Formulation; Results: GSK923295A in Vivo Testing; Table II; Figures 3/4; Discussion

Objective response and event-free-survival distributions in solid tumors: Ten mice per solid-tumor control/treatment group. EFS event: tumor-volume quadrupling; exact log-rank test, two-sided, without multiple-comparison adjustment. Objective response = PR/CR/MCR under paper definitions. — In Vivo Testing Results; Table II; Figure 3; response/EFS and statistical methods

Treatment-associated mortality and evaluability: n denotes animals in the reported treated-panel mortality totals, not biological replicate assays. ALL groups initially used eight mice per control/treatment group. — First two paragraphs of In Vivo Testing Results; Overall Group Response methods

Best objective response in neuroblastoma xenografts: PD2 denotes progressive disease with growth delay under the paper response definitions. — In Vivo Testing Results after Table II; Figure 3; Discussion

Solid tumor panel · In Vivo Tumor Growth Inhibition Studies; Drugs and Formulation; GSK923295A in Vivo Testing Results; Discussion

ALL panel toxicity · In Vivo Tumor Growth Inhibition Studies; Drugs and Formulation; GSK923295A in Vivo Testing Results; Discussion

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 1088965-37-0
Applications CENP-E inhibitor
Formula C32H38ClN5O4
Molecular Weight 592.13
SMILES
C[C@@H](C1=CC=CN2C1=NC(=C2)C3=CC=C(C=C3)C[C@@H](CNC(=O)CN(C)C)NC(=O)C4=CC(=C(C=C4)OC(C)C)Cl)O

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 90 mg/mL (151.99 mM)
Water Insoluble
Ethanol 90 mg/mL (151.99 mM)

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Wood KW, Lad L, Luo L, et al. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E Proceedings of the National Academy of Sciences of the United States of America (2010). PMID: 20167803 DOI: 10.1073/pnas.0915068107 Source material
  2. [2] Zhou AS, Tucker JB, Scribano CM, et al. Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles PLoS biology (2023). PMID: 37883329 DOI: 10.1371/journal.pbio.3002339 Source material
  3. [3] Lock RB, Carol H, Morton CL, et al. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program Pediatric blood & cancer (2012). PMID: 21584937 DOI: 10.1002/pbc.23176 Source material

Publications

1 publication citing this product

  1. Amber S Zhou, .et al. , PLoS Biol, 2023, Oct 26;21(10):e3002339 PMID: 37883329

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