Table 1. SAR of Active-Site Inhibitors with the C40-Ether Chemical Handle.
| entry | compound no. | X | PEG repeats | active-site inhibitor | pS6K IC50 (nM) | p4EBP1 IC50 (nM) | pAKT IC50 (nM) | selectivity |
|---|---|---|---|---|---|---|---|---|
| 1 | 3 (RapaLink-1)50 | O | 8 | MLN | 0.93 | 1.7 | 6.7 | 3.9 |
| 2 | 4 (everolimus) | 0.07 | >1000 | >1000 | ||||
| 3 | 5 (sapanisertib) | 0.69 | 19 | 1.8 | 0.1 | |||
| 4 | 16 (RMC-4287) | C | 8 | MLN | 0.42 | 1.1 | 3.1 | 2.8 |
| 5 | 17(51) | O | 8 | PP242 | 0.47 | 2.5 | 24 | 9.6 |
| 6 | 18 (RMC-4627) | C | 8 | PP242 | 0.28 | 1.4 | 18 | 12.9 |
| 7 | 6 (PP242) | 33 | 320 | 38 | 0.1 | |||
| 8 | 19 | C | 8 | BGT226 | 0.02 | 0.06 | 0.52 | 8.7 |
| 9 | 7 (BGT226) | 0.27 | 4.4 | 1.4 | 0.3 | |||
| 10 | 20 | C | 8 | PP121 | 0.22 | 1.0 | 17 | 17.0 |
| 11 | 8 (PP121) | 86 | >1000 | 100 | ||||
| 12 | 21 | C | 8 | “rigid MLN” | 0.13 | 0.44 | 8.8 | 20.0 |
| 13 | 22 | C | 8 | “modified-MLN” | 0.16 | 0.67 | 1.8 | 2.7 |
| 14 | 23 | C | 8 | “Me2-MLN” | 0.29 | >1000 | >1000 |