Overview on physicochemical properties as well as kinase inhibition and degradation potencies of BRAFV600E-targeting PROTACs.
| Cmpd | Linker atoms | TPSAa | elog Db | %PPBc | IC50d (nM) | D BRAF e |
|---|---|---|---|---|---|---|
| GW5074 | — | 49 | 2.3 | n.d.f | 5.8 | n.d. |
| 15a | 10 | 288 | 2.3 | 95% | 8.5 | >95% |
| 15b | 16 | 297 | 2.4 | 95% | 0.31 | >95% |
| 15c | 20 | 288 | 3.7 | 96% | 48 | >95% |
| 16a | 17 | 288 | 3.6 | 96% | 10 | 77% |
| 16b | 13 | 297 | 2.5 | 96% | 3.4 | 73% |
| 16c | 16 | 297 | 2.7 | 96% | 3.8 | 77% |
a
Topological polar surface area given in Å2.
b
Experimental distribution coefficient at pH 7.4.23
c
Protein binding values were estimated by an HPLC-based method.24
d
In vitro BRAFV600E inhibition employing a radiometric assay using 10 μM [33P]-ATP and 1 μM substrate peptide,25 see also Fig. S8.†
e
Degradation indicated as remaining BRAFV600E levels after 4 h treatment with 1 μM of each compound (as determined by densitometric analysis of Western blot assays).
f
Not determined.