Table 2.
Experimental and computational Mcl-1 and Bcl-xL inhibitory profiles of second-generation inhibitors. Experimental data determined by a fluorescence polarization competition assay.
| Compound | R2 | R3 | Mcl-1 Ki (μM)a |
Bcl-xL Ki (μM)a |
Selectivityb | Mcl-1 LGFE (kcal mol-1) |
Bcl-xL LGFE (kcal mol-1) |
|---|---|---|---|---|---|---|---|
| 3ba | iBu | iPr | 0.487 ± 0.035 | 6.08 ± 0.81 | 12 | -39 | -36 |
| 3bb | H | Ph | 1.15 ± 0.28 | ND | - | -44 | |
| 3bc | H | 4-Me-C6H4 | 0.335 ± 0.027 | 0.84 ± 0.05 | 2.5 | -44 | -43 |
| 3bd | H | 1-Naphthyl | 0.082 ± 0.012 | 0.22 ± 0.06 | 3.7 | -47 | -48 |
| 3be | H | 3-Br-C6H4 | 0.114 ± 0.017 | 0.30 ± 0.04 | 3.8 | -45 | -44 |
| 3bf | H | 3,5-di-Me-C6H3 | 0.284 ± 0.125 | 0.39 ± 0.10 | 1.4 | -46 | -46 |
| 3bg | H | 2,4-di-Cl-C6H3 | 0.079 ± 0.010 | 0.19 ± 0.02 | 2.4 | -47 | -46 |
| 3bh | H | 4-Cl-C6H4 | 0.173 ± 0.070 | ND | - | -46 | |
| 3bi | H | 4-Cl-3,5-di-Me-C6H2 | 0.117 ± 0.060 | 0.48 ± 0.05 | 4.1 | -47 | -47 |
| 3bj | iBu | 4-Cl-3,5-di-Me-C6H2 | 0.080 ± 0.019 | 0.17 ± 0.06 | 2.1 | -48 | -47 |
| 3bk | Cp | 4-Cl-3,5-di-Me-C6H2 | 0.033 ± 0.025 | 0.29 ± 0.05 | 8.8 | -40 | -39 |
| 3bl | Bn | 4-Cl-3,5-di-Me-C6H2 | 0.031 ± 0.017 | 0.34 ± 0.13 | 11 | -52 | -51 |
a
Ki values determined by Nikolovska-Coleska equation from IC50 values.50 Data represent the average of at least two independent assays; errors are standard deviations.
b
Selectivity is defined as the Ki (Bcl-xL) divided by the Ki (Mcl-1). ND, not determined.