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Fig. 1 · Structure
Cat. No.
A10981
CAS No.
639089-54-6
Formula
C23H28N8OS
Mol. Weight
464.6

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Tozasertib (VX-680, MK-0457)

Cat. No. A10981 CAS 639089-54-6

Aurora Kinase inhibitor

VX-680 is a potent and selective small-molecule inhibitor of the Aurora kinases.

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Publications for Tozasertib

3 publications citing this product

  1. Helen E. Grimsley, .et al. , bioRxiv, 2024, Jan 23
  2. Sakamoto K, .et al. , Leukemia, 2018, May 23 PMID: 29795241
  3. W. Joost Lesterhuis, .et al. , Sci Rep, 2015, 5: 12298 PMID: 26193793
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Biological Activity

Bioactivity / Mechanism

VX-680 occupies the ATP-binding site in an Aurora A–TPX2 cocrystal structure resolved at 2.3 Å. Aurora A adopts an active conformation in this complex. The comparison with a previously reported inactive complex also differs in phosphorylation state, limiting attribution of the binding-mode change solely to TPX2. [1]

In recombinant ADP-Glo assays, tozasertib inhibited human Aurora A and Aurora B with reported IC50 values of 0.030 and 0.068 µM, respectively, and also inhibited RIPK1 (IC50 0.18 µM). These assay-specific results qualify its target selectivity; they are not Ki values or cellular treatment doses. [2]

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

Target & Activity

Target Activity Value
Aurora A (Cell-free assay) 0.6 nM(Ki app)
Aurora C (Cell-free assay) 4.6 nM(Ki app)
Aurora B (Cell-free assay) 18 nM(Ki app)
FLT3 (Cell-free assay) Ki 30 nM
Bcr-Abl (Cell-free assay) Ki 30 nM

Cellular Effect

Cell Line Activity Value Description Reference
A-431 IC50 0.24 μM Antiproliferative activity against human A431 cells after 48 hrs by CCK8 assay [PMID: 29358147]
A-431 IC50 0.24 μM Antiproliferative activity against human A431 cells assessed as cell viability after 72 hrs by CCK8 assay [PMID: 24681066]
A549 IC50 15.06 μM Anticancer activity against human A549 cells assessed as reduction in cell viability measured after 24 hrs by MTT assay [PMID: 35476959]
A549 IC50 19.4 μM Cytotoxicity against human A549 cells after 48 hrs by MTT assay [PMID: 25812967]
A549 IC50 3.05 μM Antiproliferative activity against human A549 cells assessed as cell viability after 72 hrs by CCK8 assay [PMID: 24681066]
A549 IC50 3.9 μM Antiproliferative activity against human A549 cells assessed as reduction in cell viability after 72 hrs by MTT assay [PMID: 31862411]
A549 IC50 35.8 μM Antiproliferative activity against human A549 cells after 48 hrs by MTT assay [PMID: 30728112]
A549 GI50 35.8 μM Antiproliferative activity against human A549 cells after 48 hrs by MTT assay [PMID: 30502115]
A549 IC50 6.9 μM Antiproliferative activity against human A549 cells incubated for 72 hrs by MTT assay [PMID: 32941989]
COLO 205 IC50 0.019 μM Antiproliferative activity against human COLO205 cells by [3H]thymidine uptake assay [PMID: 19447622]
DU-145 IC50 0.4 μM Antiproliferative activity against human DU145 cells assessed as cell viability after 72 hrs by CCK8 assay [PMID: 24681066]
HCT-116 IC50 0.3 μM Cytotoxicity against human HCT116 cells after 48 hrs by MTT assay [PMID: 22572580]
HCT-116 IC50 0.45 μM Cytotoxicity against human HCT116 cells assessed as reduction in cell viability after 48 hrs by MTT assay [PMID: 30143423]
HCT-116 IC50 1.49 μM Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability after 72 hrs by MTT assay [PMID: 31862411]
HCT-116 EC50 120 nM Antiproliferative activity against human HCT116 cells after 96 hrs by MTS assay [PMID: 23808327]
HCT-116 IC50 120 nM Cytotoxicity against human HCT116 cells by MTS assay [PMID: 20550212]
HCT-116 IC50 2.79 μM Antiproliferative activity against human HCT116 cells incubated for 72 hrs by MTT assay [PMID: 32941989]
HCT-116 IC50 24 nM Cytotoxicity against human HCT116 cells assessed as number of colonies after 10 to 14 days by colony forming assay [PMID: 19143567]
HCT-116 IC50 4.32 μM Antiproliferative activity against human HCT116 cells after 48 hrs by CCK8 assay [PMID: 29358147]
HCT-116 IC50 4.32 μM Antiproliferative activity against human HCT116 cells assessed as cell viability after 72 hrs by CCK8 assay [PMID: 24681066]

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In Vitro Studies

VX680 reduced renal-cell carcinoma viability after 96 h in an MTT assay. Reported IC50 values were 0.367 ± 0.140 µmol/L for A498 and 0.482 ± 0.166 µmol/L for Caki-1. A704 was less sensitive (IC50 >10 µmol/L), illustrating variation across models. [3]

VX-680 binding to the Aurora A–TPX2 complex

Biochemical assay · Purified human Aurora A kinase-domain/TPX2 complex; X-ray crystallography (PDB 3e5a). [1]

VX-680 occupies the ATP-binding site of Aurora A in an active conformation in the TPX2 complex. Ligand electron density and hinge contacts support the binding assignment. TPX2-dependent changes cannot be separated cleanly from phosphorylation-state differences using the published comparison.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Aurora A/TPX2/VX-680 crystal structureDiffraction resolution 2.3 Å[1]

Literature-Reported Treatment Conditions

Treatment concentration
Compound:protein molar ratio 5:1 during complex preparation
Exposure duration
16 h at 4°C before concentration for crystallization
Method
Cocrystallization and X-ray structure determination
Co-treatment
TPX2 is a protein binding partner, not a second drug.
Reported limits
VX-680 supplier, salt state and solvent are not specified in the selected preparation method. No new inhibition constant is assigned by this structural experiment.
Methods and source locations

Compound reported in the paper: VX-680 (MK-0457, tozasertib); Compound label in the paper: VX-680; chemical structure depicted in Figure 2a; no salt specified

Applies to the named material tested in this publication; salt state is not specified. This is not validation of an Adooq lot.

Results; Figure 2a,b; Table 1; Discussion; Materials and Methods, Crystallization and structure determination

Aurora A/TPX2/VX-680 crystal structure: X-ray diffraction and structure refinement; Table 1. — Table 1; Materials and Methods, Crystallization and structure determination

Aurora A/B inhibition with direct RIPK1 activity

Biochemical assay · Recombinant human Aurora A (25 nM), Aurora B (25 nM) and RIPK1 (100 nM). [2]

Tozasertib inhibited all three recombinant kinases. Nec1s inhibited RIPK1 while the inactive analogue UAMC3132 lacked activity against the three kinases. This assay demonstrates additional RIPK1 activity and does not establish exclusive Aurora selectivity. Figure 3a–c reports mean ± SEM, n = 2; the Methods identify these as independent experiments.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Inhibition of recombinant human Aurora A kinase activityIC50 0.030 µM[2]
Inhibition of recombinant human Aurora B kinase activityIC50 0.068 µM[2]
Inhibition of recombinant human RIPK1 kinase activityIC50 0.18 µM[2]

Literature-Reported Treatment Conditions

Treatment concentration
Concentration-response experiment; see Figure 3a–c
Exposure duration
Primary kinase reaction: 4 h at room temperature
Method
Recombinant enzyme activity measured by ADP-Glo and normalized to control activity
Co-treatment
Single-compound Tozasertib curves; Nec1s and analogues are comparators, not combinations.
Reported limits
ATP concentration and assay-specific final vehicle concentration are not stated in the reported ADP-Glo method; values are assay-specific IC50 endpoints, not treatment doses or Ki values.
Methods and source locations

Compound reported in the paper: VX-680 (MK-0457, tozasertib); Compound label in the paper: Tozasertib (LC Laboratories, T-2304); no salt specified

Applies to the named material tested in this publication; salt state is not specified. This is not validation of an Adooq lot.

Results, Potency and specificity ranking… recombinant kinase profiling; Figure 3a–c; Methods, Cell culture, cytokines and reagents / In vitro ADP-Glo kinase assay / Statistics

Inhibition of recombinant human Aurora A kinase activity: ADP-Glo kinase assay; four-parameter nonlinear fitting with fixed top and bottom. — Results recombinant profiling paragraph; Figure 3b; Statistics

Inhibition of recombinant human Aurora B kinase activity: ADP-Glo kinase assay; four-parameter nonlinear fitting with fixed top and bottom. — Results recombinant profiling paragraph; Figure 3c; Statistics

Inhibition of recombinant human RIPK1 kinase activity: ADP-Glo kinase assay; four-parameter nonlinear fitting with fixed top and bottom. — Results recombinant profiling paragraph; Figure 3a; Statistics

Concentration-dependent RCC viability responses

Cell-based study · Eleven human renal-cell carcinoma lines, including A498 and Caki-1; the paper identifies Caki-2 and SKRC39 as papillary RCC. [3]

After 96 h, VX680 reduced MTT viability in the RCC panel relative to DMSO controls. A498 and Caki-1 were among the more sensitive models; A704 had an IC50 greater than 10 µmol/L. These model-dependent MTT responses do not by themselves identify the mechanism of cell death. The paper uses mean ± SD for statistical reporting but does not state an experimental n for these IC50 estimates.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
A498 MTT viability relative to DMSO control at 96 hIC50 0.367 ± 0.140 µmol/L[3]
Caki-1 MTT viability relative to DMSO control at 96 hIC50 0.482 ± 0.166 µmol/L[3]
A704 MTT viability relative to DMSO control at 96 hIC50 >10 µmol/L[3]

Literature-Reported Treatment Conditions

Treatment concentration
Various VX680 concentrations; Figure 1c displays concentration-response curves for A498 and Caki-1.
Exposure duration
96 h
Method
MTT viability assay compared with DMSO-treated cells
Vehicle
DMSO control
Co-treatment
VX680 alone
Reported limits
Final DMSO percentage, VX680 supplier, salt state and number of independent replicates for these estimates are not stated in the selected assay report.
Methods and source locations

Compound reported in the paper: VX-680 (MK-0457, tozasertib); Compound label in the paper: VX680 (also referred to as MK-0457); no salt specified

Applies to the named material tested in this publication; salt state is not specified. This is not validation of an Adooq lot.

Methods, Analysis of cell proliferation and viability / Statistical analysis; Results, VX680 directly reduced the viability…; Figure 1b,c

A498 MTT viability relative to DMSO control at 96 h: MTT absorbance at 540 nm; paper general reporting convention: mean ± SD; n not specified. — Results, VX680 directly reduced the viability…; Figure 1b,c; Statistical analysis

Caki-1 MTT viability relative to DMSO control at 96 h: MTT absorbance at 540 nm; paper general reporting convention: mean ± SD; n not specified. — Results, VX680 directly reduced the viability…; Figure 1b,c; Statistical analysis

A704 MTT viability relative to DMSO control at 96 h: MTT concentration-response assay; operator preserved from Results. — Results, VX680 directly reduced the viability…; Figure 1b

In Vivo Studies

In an AB1-HA mesothelioma mouse model, sequential VX-680 plus anti-CTLA4 improved survival relative to anti-CTLA4 alone. The VX-680 dose was 80 mg/kg i.p. daily for 10 days, beginning 5 days after anti-CTLA4. The authors separately reported substantial toxicity, including sterile peritoneal inflammation leading to bowel obstruction, with simultaneous administration. [4]

Sequential VX-680 and anti-CTLA4 in mesothelioma

Animal study · Female BALB/c mice, 8–12 weeks old, bearing subcutaneous AB1-HA mesothelioma. [4]

The sequential VX-680 plus anti-CTLA4 regimen improved Kaplan–Meier survival (with a tumor-size humane euthanasia endpoint) relative to anti-CTLA4 alone in Figure 4b. PBS and VX-680-only groups were included. The caption describes a representative experiment from three independent experiments, with n = 10 mice per arm. Separately, the Methods report substantial toxicity with simultaneous administration, prompting the sequential schedule; this toxicity is not an outcome of the plotted sequential arm.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Survival with tumor-size humane euthanasia endpoint: sequential VX-680 plus anti-CTLA4 compared with anti-CTLA4 aloneLog-rank comparison P < 0.05[4]
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
PBS controlControl groupControl survival curve shown in Figure 4b.[4]
Anti-CTLA4 alone
100 µg/mouse		PBSComparator for the significant sequential-combination survival improvement.[4]
VX-680 alonePBSSingle-agent survival curve shown; no significant single-agent benefit claimed.[4]
Sequential anti-CTLA4 then VX-680
Anti-CTLA4: 100 µg/mouse; VX-680: 80 mg/kg		Anti-CTLA4 alone; PBS and VX-680 alone also shownImproved survival versus anti-CTLA4 alone (P < 0.05).[4]
PBS control
Model: Female BALB/c mice, 8–12 weeks old, bearing subcutaneous AB1-HA mesothelioma.
Reported limits: Final injection vehicle composition is not fully specified; no precise curve-derived survival fraction is assigned.
Anti-CTLA4 alone
Model: Female BALB/c mice, 8–12 weeks old, bearing subcutaneous AB1-HA mesothelioma.
Route: Intraperitoneal
Frequency: Single dose
Treatment course: Day 10
Reported limits: Final injection vehicle composition is not fully specified; no precise curve-derived survival fraction is assigned.
VX-680 alone
Model: Female BALB/c mice, 8–12 weeks old, bearing subcutaneous AB1-HA mesothelioma.
Reported limits: VX-680-only comparator is shown in Figure 4b, but its separate dosing dates and duration are not unambiguously specified apart from the sequential-combination description. No arm-specific schedule is assigned.
Sequential anti-CTLA4 then VX-680
Model: Female BALB/c mice, 8–12 weeks old, bearing subcutaneous AB1-HA mesothelioma.
Route: Intraperitoneal
Frequency: Anti-CTLA4 once; VX-680 daily
Treatment course: Anti-CTLA4 day 10; VX-680 for 10 days beginning 5 days later
Reported limits: Final injection vehicle composition is not fully specified; no precise curve-derived survival fraction is assigned.
Methods and source locations

Compound reported in the paper: VX-680 (MK-0457, tozasertib); Compound label in the paper: VX-680 (AdooQ Bioscience, CA, USA); no salt or catalog number specified

Applies to the named material tested in this publication; salt state is not specified. This is not validation of an Adooq lot.

Results, Pharmacological modulation… final AURKB paragraph; Figure 4b and caption; Methods, Drugs and treatment schedules for in vivo treatment / Statistical Analyses of Mouse Experiments

Survival with tumor-size humane euthanasia endpoint: sequential VX-680 plus anti-CTLA4 compared with anti-CTLA4 alone: Kaplan–Meier survival; Figure 4b, representative of three independent experiments; n = 10 mice per arm. No exact survival percentage is inferred from the curve. — Figure 4b and caption; Statistical Analyses of Mouse Experiments

PBS control · Results, Pharmacological modulation… final AURKB paragraph; Figure 4b and caption; Methods, Drugs and treatment schedules for in vivo treatment / Statistical Analyses of Mouse Experiments

Anti-CTLA4 alone · Results, Pharmacological modulation… final AURKB paragraph; Figure 4b and caption; Methods, Drugs and treatment schedules for in vivo treatment / Statistical Analyses of Mouse Experiments

VX-680 alone · Results, Pharmacological modulation… final AURKB paragraph; Figure 4b and caption; Methods, Drugs and treatment schedules for in vivo treatment / Statistical Analyses of Mouse Experiments

Sequential anti-CTLA4 then VX-680 · Results, Pharmacological modulation… final AURKB paragraph; Figure 4b and caption; Methods, Drugs and treatment schedules for in vivo treatment / Statistical Analyses of Mouse Experiments

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 639089-54-6
Applications Aurora Kinase inhibitor
Formula C23H28N8OS
Molecular Weight 464.6
Synonyms VX-680; MK-0457
SMILES
CC1=CC(=NN1)NC2=NC(=NC(=C2)N3CCN(CC3)C)SC4=CC=C(C=C4)NC(=O)C5CC5

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 90 mg/mL (193.71 mM)
Water Insoluble
Ethanol Insoluble

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.

In Vivo Preparation

Concentration
14 mg/mL
Vehicle
5% DMSO+30% PEG 300+2% Tween 80+ddH2O

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] Zhao B, Smallwood A, Yang J, et al. Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2 Protein science : a publication of the Protein Society (2008). PMID: 18662907 DOI: 10.1110/ps.036590.108 Source material
  2. [2] Martens S, Goossens V, Devisscher L, et al. RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib (VX-680) Cell death & disease (2018). PMID: 29434255 DOI: 10.1038/s41419-017-0245-7 Source material
  3. [3] Li Y, Zhang ZF, Chen J, et al. VX680/MK-0457, a potent and selective Aurora kinase inhibitor, targets both tumor and endothelial cells in clear cell renal cell carcinoma American journal of translational research (2010). PMID: 20589168 Source material
  4. [4] Lesterhuis WJ, Rinaldi C, Jones A, et al. Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations Scientific reports (2015). PMID: 26193793 DOI: 10.1038/srep12298 Source material

Publications

3 publications citing this product

  1. Helen E. Grimsley, .et al. , bioRxiv, 2024, Jan 23
  2. Sakamoto K, .et al. , Leukemia, 2018, May 23 PMID: 29795241
  3. W. Joost Lesterhuis, .et al. , Sci Rep, 2015, 5: 12298 PMID: 26193793

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