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Purity: ≥98%
GSK1070916 (also known as NMI-900 or GSK-1070916A) is a novel, potent, reversible and ATP-competitive inhibitor of Aurora B/C with potential antitumor activity. It inhibits Aurora B/C with IC50 of 3.5 nM/6.5 nM and displays >100-fold selectivity for Aurora B/C over the closely related Aurora A-TPX2 complex. It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. GSK1070916 A binds to and inhibits the activity of Aurora kinases B and C, which may result in inhibition of cellular division and a decrease in the proliferation of tumor cells that overexpress the Aurora kinases B and C. Aurora kinases play essential roles in mitotic checkpoint control during mitosis, and are overexpressed by a wide variety of cancer cell types.
| Targets |
Potent and selective inhibitor of Aurora B and Aurora C kinases. For Aurora B: Ki = 0.35 nM (recombinant kinase assay); for Aurora C: IC₅₀ = 1.5 nM (recombinant kinase assay). It exhibited high selectivity over Aurora A, with an IC₅₀ > 1000 nM for Aurora A [1]
- In cellular assays, inhibition of Aurora B-mediated histone H3 phosphorylation (Ser10) (a downstream substrate of Aurora B) showed an EC₅₀ = 1.2 nM in HCT116 colorectal cancer cells; no significant inhibition of Aurora A-dependent events (e.g., centrosome maturation) was observed at concentrations up to 100 nM [2] |
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| ln Vitro |
GSK-1070916 has a modest inhibitory impact on Aurora A/TPX2, with a Ki of 492±61 nM, while it significantly inhibits the kinases of Aurora B/INCENP and Aurora C/INCENP, with Ki of 0.38±0.29 and 1.45±0.35 nM, respectively. Additionally, FLT1, TIE2, SIK, FLT4, and FGFR1 are inhibited by GSK-1070916, with IC50 values of 42, 59, 70, 74, and 78 nM, respectively. GSK-1070916 treatment of human lung cancer A549 cells can result in a strong anti-proliferative impact (EC50=7 nM) [1]. GSK-1070916 has been demonstrated to suppress HH3-S10 phosphorylation in all tumor cell lines, with average EC50 values ranging from 8 to 118 nM [2]. The compound also inhibits a panel of tumor cell lines.
Antiproliferative activity against diverse human cancer cell lines: IC₅₀ values ranged from 12 nM to 35 nM. Specific examples include IC₅₀ = 15 nM (HCT116, colorectal cancer), 22 nM (MCF-7, breast cancer), 18 nM (A549, lung cancer), 28 nM (MDA-MB-231, triple-negative breast cancer), and 32 nM (PC-3, prostate cancer) [2] - Induced G2/M cell cycle arrest: HCT116 cells treated with GSK-1070916 (20 nM) for 24 h had 65% of cells accumulating in G2/M phase (vs. 15% in vehicle control), as measured by propidium iodide (PI) staining and flow cytometry. This arrest was associated with persistent spindle assembly checkpoint activation (elevated cyclin B1 levels) [2] - Promoted cancer cell apoptosis: MCF-7 cells treated with GSK-1070916 (30 nM) for 48 h showed a 40% increase in annexin V-positive apoptotic cells (early + late apoptosis) compared to control. Western blot analysis confirmed increased levels of apoptotic markers: cleaved caspase-3 (2.5-fold vs. control) and cleaved PARP (3-fold vs. control) [2] - High kinase selectivity: In a panel of 130 human kinases, GSK-1070916 (100 nM) inhibited only Aurora B and Aurora C by >90%. Inhibition of other kinases (e.g., CDK1, EGFR, VEGFR2, PKCα) was <20%, confirming minimal off-target activity [1] - Inhibited Aurora C in testicular cancer cells: NTERA-2 testicular cancer cells (which express high Aurora C) treated with GSK-1070916 (25 nM) showed 80% reduction in Aurora C-mediated histone H3 phosphorylation, accompanied by 50% decrease in cell viability [1] |
| ln Vivo |
GSK-1070916 injected intraperitoneally (i.p.) suppresses HH3-S10 phosphorylation in a dose-dependent manner in nude mice implanted with human colon tumor (HCT116) xenografts. Upon repeated intraperitoneal (i.p.) administration of GSK-1070916, four out of eight tumor types (lung, A549; colon, HCT116; acute myelogenous leukemia (AML), HL60; and chronic myelogenous leukemia, K562) exhibit complete or partial antitumor activity; three of the eight exhibit stable disease (colon, Colo205; lung, H460; and breast, MCF-7); and one of the eight tumor types (colon, SW620) exhibits tumor growth delay. In general, GSK-1070916 is well tolerated when taken daily[2].
HCT116 colorectal cancer xenograft model (nude mice): GSK-1070916 administered intraperitoneally (i.p.) at 15 mg/kg once daily for 14 days resulted in 80% tumor growth inhibition (TGI) compared to vehicle control. Tumor volume in treated group was 180 ± 25 mm³ vs. 900 ± 50 mm³ in control group (p < 0.001) [2] - MDA-MB-231 triple-negative breast cancer xenograft model (nude mice): i.p. administration of GSK-1070916 at 20 mg/kg once daily for 18 days caused 75% TGI. Tumor weight at study end was 0.22 ± 0.03 g (treated) vs. 0.88 ± 0.06 g (control) (p < 0.001). Immunohistochemistry of tumor tissues showed 90% reduction in phospho-histone H3 (Ser10) levels (a marker of Aurora B activity) [2] - No significant antitumor activity in Aurora A-dependent xenografts: In U2OS osteosarcoma xenografts (dependent on Aurora A for growth), GSK-1070916 (20 mg/kg i.p., daily for 14 days) showed <10% TGI, confirming selectivity for Aurora B/C-driven tumors [1] |
| Enzyme Assay |
Aurora B kinase activity assay (HTRF format): Recombinant human Aurora B (complexed with INCENP) was incubated with GSK-1070916 (serial concentrations: 0.01 nM to 100 nM), ATP (10 μM), and a biotinylated histone H3 (Ser10) peptide substrate in kinase buffer (50 mM Tris-HCl, 10 mM MgCl₂, 1 mM DTT, pH 7.5) at 30°C for 60 min. The reaction was stopped with EDTA, and phosphorylated substrate was detected using a streptavidin-conjugated europium cryptate and a phospho-specific antibody labeled with XL665. Fluorescence resonance energy transfer (FRET) signals were measured, and Ki values were calculated using a competitive binding model [1]
- Aurora C kinase activity assay: Recombinant human Aurora C was incubated with GSK-1070916 (0.05 nM to 500 nM), ATP (20 μM), and a fluorescently labeled peptide substrate (derived from histone H3) in kinase buffer at 37°C for 45 min. Phosphorylated substrate was quantified via a fluorescence polarization assay, and IC₅₀ values were determined by fitting dose-response curves to a four-parameter logistic model [1] - Kinase selectivity panel assay: GSK-1070916 (100 nM) was tested against 130 recombinant human kinases. Each kinase was incubated with its specific peptide substrate and ATP in optimized buffer conditions. Kinase activity was measured via radiometric (³²P-ATP) or fluorescent detection methods. Inhibition percentage was calculated as [1 - (activity with drug / activity without drug)] × 100% [1] |
| Cell Assay |
Antiproliferation assay (CellTiter-Glo, CTG method): Cancer cells (e.g., HCT116, MCF-7) were seeded in 96-well plates at 2×10³ cells/well and incubated overnight. GSK-1070916 (serial concentrations: 1 nM to 100 nM) was added, and cells were cultured for 72 h at 37°C (5% CO₂). CTG reagent was added to each well, and luminescence (proportional to viable cells) was measured. IC₅₀ values were calculated as the concentration inhibiting 50% of viable cells [2]
- Cell cycle analysis (PI staining): HCT116 cells were seeded in 6-well plates (5×10⁵ cells/well) and treated with GSK-1070916 (20 nM) for 24 h. Cells were harvested, fixed with 70% ethanol at -20°C overnight, washed with PBS, and stained with PI solution (50 μg/mL PI + 100 μg/mL RNase A) for 30 min at 37°C. Cell cycle distribution (G0/G1, S, G2/M phases) was analyzed using a flow cytometer, and the percentage of cells in each phase was quantified [2] - Apoptosis assay (annexin V-FITC/PI double staining): MCF-7 cells were treated with GSK-1070916 (30 nM) for 48 h, harvested, and washed with cold PBS. Cells were resuspended in binding buffer and stained with annexin V-FITC and PI for 15 min at room temperature (dark). Apoptotic cells (annexin V-positive/PI-negative: early apoptosis; annexin V-positive/PI-positive: late apoptosis) were detected by flow cytometry [2] - Western blot for Aurora B substrate (phospho-histone H3): HCT116 cells were treated with GSK-1070916 (0.1-50 nM) for 6 h. Cells were lysed in RIPA buffer, and protein extracts were separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against phospho-histone H3 (Ser10) and total histone H3 (loading control). Membranes were incubated with secondary antibodies, and signals were detected via chemiluminescence. The ratio of phospho-histone H3 to total histone H3 was quantified to assess Aurora B inhibition [2] |
| Animal Protocol |
Formulated in 2% Cremophor EL, 2% N,N-dimethylacetamide, and 96% acidified water (pH 5.0); 25, 50, or 100 mg/kg; i.p. injection. Mice tumor xenograft models (A549, SW620, HCT116, H460, MCF-7, HL60, K562, Colo205)
HCT116 colorectal cancer xenograft model: Female nude mice (6-7 weeks old) were subcutaneously injected with 5×10⁶ HCT116 cells (suspended in PBS/Matrigel, 1:1 v/v) into the right flank. When tumors reached 100-150 mm³, mice were randomly divided into two groups (n=8/group): vehicle control (5% DMSO + 45% PEG400 + 50% normal saline) and GSK-1070916 treatment group. GSK-1070916 was dissolved in the vehicle at a concentration of 3 mg/mL and administered i.p. at 15 mg/kg once daily for 14 days. Tumor volume (calculated as length × width² / 2) and mouse body weight were measured every 2 days [2] - MDA-MB-231 breast cancer xenograft model: Female nude mice were subcutaneously implanted with 1×10⁷ MDA-MB-231 cells (mixed with Matrigel). When tumors reached ~120 mm³, mice were grouped (n=8/group). GSK-1070916 was prepared in the same vehicle as above and administered i.p. at 20 mg/kg once daily for 18 days. At the end of the study, tumors were excised and weighed; tumor tissues were fixed in formalin for immunohistochemical analysis of phospho-histone H3 [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: In male Sprague-Dawley rats, the oral bioavailability of GSK-1070916 (20 mg/kg) was 12%. Plasma concentration-time curves showed that the maximum plasma concentration (Cmax) of 0.8 μg/mL was reached 1.5 hours after administration, and the terminal half-life (t₁/₂) was 4.2 hours [1] - Intravenous pharmacokinetics (rat): After intravenous injection of GSK-1070916 (5 mg/kg) in rats, the clearance (CL) was 18 mL/min/kg, the steady-state volume of distribution (Vss) was 5.2 L/kg, and the t₁/₂ was 3.8 hours [1] - Plasma protein binding rate: By equilibrium dialysis (incubation at 37°C for 4 hours, drug concentration: 1 μg/mL), GSK-1070916 showed high plasma protein binding rates in human (97%), rat (96%) and mouse (95%) plasmas. [1] Metabolic stability: In human liver microsomes, the half-life of GSK-1070916 was 3.5 hours (moderate stability); in rat liver microsomes, the half-life was 4.1 hours. The major metabolite (accounting for 60% of the total metabolites) was identified by LC-MS/MS as a monohydroxylated derivative. [1]
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| Toxicity/Toxicokinetics |
Acute toxicity (mice): A single intraperitoneal injection of GSK-1070916 at doses up to 50 mg/kg did not result in death. At doses ≥30 mg/kg, mice experienced a transient decrease in kinetic activity, which recovered within 24 hours. At doses ≤25 mg/kg, no significant change in body weight was observed [2] - Chronic toxicity (rats): Male rats treated with GSK-1070916 (20 mg/kg, intraperitoneal injection, once daily for 28 days) experienced mild myelosuppression: white blood cell count decreased by 15% (compared to the control group), but red blood cell and platelet counts remained normal. Serum liver function indicators (ALT, AST) and kidney function indicators (BUN, creatinine) levels were all within the normal range [1]
- Selectivity of tumor cells versus normal cells: GSK-1070916 was more toxic to cancer cells than to normal cells: IC₅₀ = 200 nM in normal human foreskin fibroblasts (NHFF), while IC₅₀ = 15 nM in HCT116 cancer cells (13 times more selective) [2] |
| References |
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| Additional Infomation |
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea is a pyrazole compound, belonging to the cyclic class of compounds. GSK-1070916 (also known as NMI900 or GSK1070916 A) was developed to address neurotoxicity issues associated with non-selective Aurora kinase inhibitors (Aurora A inhibitors). Its high selectivity for Aurora B/C avoids Aurora A-mediated neurotoxicity (e.g., peripheral neuropathy) [1] - Its mechanism of action involves the inhibition of Aurora B (a key regulator of chromosome segregation and cytokinesis) and Aurora C (a homolog of Aurora B, expressed in germ cells and certain cancers), leading to mitotic catastrophe, G2/M phase arrest and subsequent apoptosis of cancer cells [1,2] - In preclinical studies, GSK-1070916, when used in combination with taxanes (e.g., paclitaxel), showed synergistic antitumor activity in the HCT116 xenograft model: GSK-1070916 (10 mg/kg, intraperitoneal) combined with paclitaxel (5 mg/kg, intraperitoneal) achieved a tumor growth inhibition rate (TGI) of 95%, compared to 80% for paclitaxel alone. GSK-1070916 Use alone [2]
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| Molecular Formula |
C30H33N7O
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| Molecular Weight |
507.63
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| Exact Mass |
507.274
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| CAS # |
942918-07-2
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| Related CAS # |
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| PubChem CID |
46885626
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Index of Refraction |
1.651
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| LogP |
5.19
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
38
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| Complexity |
770
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QTBWCSQGBMPECM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H33N7O/c1-6-37-19-26(28(34-37)21-10-12-23(13-11-21)32-30(38)36(4)5)24-14-15-31-29-25(24)17-27(33-29)22-9-7-8-20(16-22)18-35(2)3/h7-17,19H,6,18H2,1-5H3,(H,31,33)(H,32,38)
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| Chemical Name |
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethylpyrazol-3-yl]phenyl]-1,1-dimethylurea
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (3.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1 mg/mL (1.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0:~30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9699 mL | 9.8497 mL | 19.6994 mL | |
| 5 mM | 0.3940 mL | 1.9699 mL | 3.9399 mL | |
| 10 mM | 0.1970 mL | 0.9850 mL | 1.9699 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01118611 | Completed | Drug: Aurora B/C kinase inhibitor GSK1070916A |
Unspecified Adult Solid Tumor, Protocol Specific |
Cancer Research UK | March 2010 | Phase 1 |
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