VZ185 is a potent and effective degrader of BRD7 and BRD9 in cells. The activity of VZ185 has been clearly linked to the binding to BRD7 and 9 as well as VHL. Convincing time-course and dose-response data is also presented with added data clearly showing proteasome involvement as well as proteomics data showing clean’ BRD7/9 in RI-1 cells. BRD7 and 9 are close with respect to their Kd and DC50, yet a slightly shifted curve is seen between the two homologs, which is why the 1 uM dose should be the upper end of a d.r. range with perhaps 300 nM being safer to effect full degradation without the beginning of a hook effect. How this will be similar of different across cell types remains unclear, thus a dose lower than 1 uM should always be tested and perhaps 300 nM is a more relevant dose. While selectivity in an RI-1 proteomics experiment was reported it would have been nice to see a lack of binding to other family members, or a greater characterization of the negative control cis-VZ185. Cis-.VZ-185 presumably still binds to BRD7/9 but no longer effects degradation.
12 Mar 2021 )