Table 1. Small Molecule Thermostabilization of GRKs and PKA.
| GRK1 | GRK2 | GRK5 | PKA | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| rank/ΔTm (°C)a | Tm (°C) | ΔTm (°C) | Tm (°C) | ΔTm (°C) | Tm (°C) | ΔTm (°C) | Tm (°C) | ΔTm (°C) | ||
| paroxetineb | 20.4 | 0.5 | 45.3 | 7.8 | 26.8 | 0.0 | 50.1 | 4.7 | ||
| indazole class | GSK180736A | GRK2: 3/5.3 | 25.3 | 5.4 | 49.9 | 12.4 | 28.7 | 1.9 | 49.2 | 3.8 |
| GSK299115A | GRK2: 4/4.8 | 23.4 | 3.5 | 48.3 | 10.7 | 28.1 | 1.3 | 49.5 | 4.1 | |
| GSK466317A | GRK2: 8/2.9 | 24.6 | 4.7 | 45.0 | 7.4 | 28.0 | 1.3 | 50.6 | 5.2 | |
| GSK317354A | GRK2: 6/3.7 | 23.2 | 3.3 | 49.0 | 11.4 | 27.3 | 0.6 | 45.9 | 0.5 | |
| GSK270822A | GRK2: 5/3.8 | 24.6 | 4.7 | 47.8 | 10.3 | 29.4 | 2.6 | 51.9 | 6.5 | |
| pyrrolopyrimidine class | GSK2163632A | GRK5: 4/9.2 | 26.3 | 6.4 | 41.4 | 3.8 | 33.0 | 6.3 | 48.5 | 3.1 |
| GSK2110236A | GRK5: 7/8.3 | 18.5 | –1.4 | 40.6 | 3.0 | 32.6 | 5.8 | 46.6 | 1.2 | |
| GSK2220400A | GRK5: 13/6.9 | 28.6 | 8.7 | 38.8 | 1.2 | 30.5 | 3.8 | 45.4 | 0.0 | |
| GSK1713088A | GRK5: 11/7.4 | 39.1 | 19.2 | 44.2 | 6.7 | 40.3 | 13.6 | 45.8 | 0.4 | |
| GSK1326255A | GRK2: 6/3.3 | 25.1 | 5.2 | 42.4 | 4.9 | 29.3 | 2.5 | 48.5 | 3.1 | |
| other | GW693881A | GRK5: 12/6.9 | 24.8 | 4.9 | 40.0 | 2.5 | 27.7 | 0.9 | 47.4 | 2.0 |
| GW416981X | GRK5: 15/6.5 | 24.8 | 4.9 | 40.4 | 2.8 | 28.7 | 2.0 | 47.7 | 2.3 | |
| GSK1007102B | GRK2: 1/5.4 | 26.7 | 6.8 | 49.3 | 11.8 | 28.7 | 2.0 | 52.2 | 6.8 | |
| GW806742X | GRK5: 16/6.5 | 20.3 | 0.4 | 36.4 | –1.1 | 27.1 | 0.4 | 45.6 | 0.2 | |
a
Rank denotes the rank ordering of the compounds in the primary screen. ΔTm values are relative to the intrinsic melting point of each kinase, determined independently for primary and confirmation screens.
b
Paroxetine was not included in the primary screen but is included due to its structural similarity to the GSK180736A/indazole cluster of compounds and as a biochemical benchmark.