Table I.
Summary of studies using chemical inhibitors of human Mps1 kinase activity
| Property | Studies | ||||||
| Hewitt et al., 2010 | Kwiatkowski et al., 2010 | Santaguida et al., 2010 | Maciejowski et al., 2010 | Sliedrecht et al., 2010 | Tighe et al., 2008 | ||
| Inhibitor | AZ3146 | Mps1-IN-1 | Mps1-IN-2 | Reversine | 3MB-PP1 | 23-dMB-PP1 | 1-NM-PP1 |
| Structure |  |  |  |  |  |  |  |
| IC50 (nM)a | 35 | 370 | 145 | 3/6b | ND | ND | ND |
| Conc. used in cell (µM) | 2 | 10 | 10 | 0.5 | 10 | 1 | 10 |
| Drug target | Endogenous Mps1 | Endogenous Mps1 | Endogenous Mps1c | Endogenous Mps1d | Mps1-ase | Mps1-ase | Mps1-ase |
| Approach | Inhibitor; siRNA | Inhibitor; stable shRNA | Inhibitor; stable shRNA | Inhibitor; siRNA | Gene knockout + stable transgene | stable shRNA + stable transgene | shRNA + transgene |
| Cell line used | HeLa | U2OS/HCT116/HeLa/RPE1 | U2OS | HeLa | hTERT-RPE1 | U2OS/HCT116 | HeLa |
| TMitosis (min)f | ∼90 | ND | ND | ∼45 | ∼42 | ∼22/18 | ND |
| TMitosis+Inhibitor (min) | ∼32 | ∼45 | ND | ∼30 | ∼12 | ∼12/10 | ∼36 |
| Kinetochore localization inhibitedg | O-Mad2/CENP-E | Mad2/Mad1 | ND | Mad1/Spindly/Rod/Zw10/Zwilch | Mad2/Mad1/Bub1/BubR1/Zw10/Plk1/CENP-E/pH2A/Sgo1 | Mad2/Mad1 Bub1/Cdc20 | Mad2 |
| Kinetochore localization not inhibited | Mad1h/Zwilchh pCENP-A/Aurora B/pAurora B/ACA | CREST | ND | Bub1/BubR1/KNL1/Mis12/Ndc80/Zwint/Aurora B/pCENP-A/CENP-C/CREST | Ska3/Ndc80/KNL1/Zwint/CENP-A/Aurora B/INCENP/CREST | CENP-E/BubR1/ACA | Mad1/ACA |
| Chromosome misalignment | ND | Yes | ND | Yes | Yes | Yes | ND |
| Defect in error correction | Yes | NA | ND | Yes | ND | Yes | ND |
| Affect Aurora B kinase activity | No | Yes | ND | No (at 0.5 µM) | No | Yes | ND |
| Property | Studies | ||||||
| Hewitt et al., 2010 | Kwiatkowski et al., 2010 | Santaguida et al., 2010 | Maciejowski et al., 2010 | Sliedrecht et al., 2010 | Tighe et al., 2008 | ||
| Inhibitor | AZ3146 | Mps1-IN-1 | Mps1-IN-2 | Reversine | 3MB-PP1 | 23-dMB-PP1 | 1-NM-PP1 |
| Structure | | | | | | | |
| IC50 (nM)a | 35 | 370 | 145 | 3/6b | ND | ND | ND |
| Conc. used in cell (µM) | 2 | 10 | 10 | 0.5 | 10 | 1 | 10 |
| Drug target | Endogenous Mps1 | Endogenous Mps1 | Endogenous Mps1c | Endogenous Mps1d | Mps1-ase | Mps1-ase | Mps1-ase |
| Approach | Inhibitor; siRNA | Inhibitor; stable shRNA | Inhibitor; stable shRNA | Inhibitor; siRNA | Gene knockout + stable transgene | stable shRNA + stable transgene | shRNA + transgene |
| Cell line used | HeLa | U2OS/HCT116/HeLa/RPE1 | U2OS | HeLa | hTERT-RPE1 | U2OS/HCT116 | HeLa |
| TMitosis (min)f | ∼90 | ND | ND | ∼45 | ∼42 | ∼22/18 | ND |
| TMitosis+Inhibitor (min) | ∼32 | ∼45 | ND | ∼30 | ∼12 | ∼12/10 | ∼36 |
| Kinetochore localization inhibitedg | O-Mad2/CENP-E | Mad2/Mad1 | ND | Mad1/Spindly/Rod/Zw10/Zwilch | Mad2/Mad1/Bub1/BubR1/Zw10/Plk1/CENP-E/pH2A/Sgo1 | Mad2/Mad1 Bub1/Cdc20 | Mad2 |
| Kinetochore localization not inhibited | Mad1h/Zwilchh pCENP-A/Aurora B/pAurora B/ACA | CREST | ND | Bub1/BubR1/KNL1/Mis12/Ndc80/Zwint/Aurora B/pCENP-A/CENP-C/CREST | Ska3/Ndc80/KNL1/Zwint/CENP-A/Aurora B/INCENP/CREST | CENP-E/BubR1/ACA | Mad1/ACA |
| Chromosome misalignment | ND | Yes | ND | Yes | Yes | Yes | ND |
| Defect in error correction | Yes | NA | ND | Yes | ND | Yes | ND |
| Affect Aurora B kinase activity | No | Yes | ND | No (at 0.5 µM) | No | Yes | ND |
Conc., concentration.
a
The half maximal inhibitory concentration.
b
For full-length and kinase domain Mps1, respectively.
c
Binds Plk1 with higher affinity.
d
Inhibits Aurora B with an IC50 of 98 nM.
e
Analogue-sensitive Mps1.
f
Time cells spend in mitosis.
g
Scoring >50% reduction of signal intensity.
h
Depends on when drugs are applied.