Table 1.
Fold-change in IC50 relative to WT IC50 from alanine mutagenesis of hERG pore residues for selected hERG blockers.
| hERG blocker | Cell line | Temp. | WT IC50 (nM) |
Fold Increase in IC50 (mutant IC50/WT IC50) | Ref | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Pore helix | SF | S6 | |||||||||
| T623A | S624A | V625A | G648A | Y652A | F656A | V659A | |||||
| amiodarone | HEK293 | 37°C | 45 | 6.5 | 22 | 6 (E) |
5.7 | 20 | 17 | 9.9 | (Zhang et al., 2016) |
| Cavalli-2 | HEK293 | 37°C | 36 | 16 | 7 | 17 | 75 | (Helliwell et al., 2018) | |||
| clomipramine | HEK293 Oocyte |
36 °C room temp. |
130 12,400 |
6 |
12 |
(Jo et al., 2008) | |||||
| cisapride | Oocyte | room temp. | 133 | 2 | 1 | 100 | 40 | (Mitcheson et al., 2000) | |||
| clofilium | Oocyte | room temp. | 30 | 12 | 381 | 250 | 1329 | 484 | (Perry et al., 2004; Perry et al., 2006) | ||
|
dofetilide (estimated) |
Oocyte | room temp. | 420 | 7 | 9 | 130 | 171 | 25 | 62 | 3 | (Kamiya et al., 2006) |
|
E-4031 (estimated) |
Oocyte | room temp. | 570 | 4 | 13 | 86 | 40 | 31 | 89 | 4 | (Kamiya et al., 2006) |
| flecainide | HEK293 | 37 °C | 1,490 | 5.6 | 1.8 | 27.5 | 8.9 | 3.4 | 141.5 | (Melgari et al., 2015a) | |
| ibutilide | Oocyte | room temp. | 28 | 54 | 93 | >300 | 140 (E) |
67 (E) |
140 (E) |
18 (E) |
(Perry et al., 2004) |
| MK-499 | Oocyte | room temp. | 34 | 5 | 54 | 55 | 94 | 650 | (Mitcheson et al., 2000) | ||
| ranolazine | HEK293 | 37°C | 8,030 | 19 | 8 | 8 | 22 | 53 | (Du et al., 2014) | ||
| R-roscovitine | Oocyte | room temp. | 196,000 | 5.4 | 0.8 | 2.9 | 42 | (Cernuda et al., 2019) | |||
| terfenadine | Oocyte | room temp. | 134 | 1.5 | 1.5 | 150 | 100 | (Mitcheson et al., 2000) | |||
| verapamil | HEK293 Oocyte |
room temp. | 143 5,100 |
16 |
20 |
(Zhang et al., 1999; Duan et al., 2007) | |||||
| ziprasidone | HEK293 Oocyte |
37 °C room temp. |
120 2,800 |
140 |
357 |
(Su et al., 2006) | |||||
(E), estimated. The data report the effects on drug block of hERG mutations in pore helix residues, V625 in the selectivity filter (SF) or residues on the S6 helix. The fold increase in IC50 relative to its WT control is given as IC50 mutant/IC50 WT. Estimated fold increases in IC50 are tabled where experimentally derived IC50 values were not reported; the estimated values were calculated using available single dose data, by using a standard Hill equation: Fractional block = 1/(1 + (IC50/[drug])h), and assuming h = 1. Table updated from (Zhang et al., 2016).