SERP
Comments:
CST967 is currently (July 2023), alongside with with U7D-1, the best available PROTAC tool compounds targeting USP7 for degradation. It has been demonstrated that CST967 can induce (as Dmax) 85 % reduction of USP7 protein levels after 24 H treatment of MM.1S cells at 1uM concentration. Analogously, DC50 of 17 nM was determined by 24 H treatment of MM.1S. Very similar Dmax and DC50 were observed also for the alternative USP7 PROTAC compound U7D-1, which is based on similar scaffold. As a weakness of the original publications I see the evaluation of the selectivity profile by MS-proteomic analysis, which has been performed at conditions (3 H trearment time and 0.1 uM concentration) that very likely doesnt correspond to the conditions used for cellular experiment by potential users (and experiments used to determine Dmax and DC50 which were performed at 24 H treatment time). This is also reflected by the results from MS-proteomic analysis where the USP7 degradation degradation shows fold change value (-0.5 log2 FC) that is at the borderline of significance. The mechanosm of action and its dependency on ubiquitine-proteasome system has been evaluated and confirmed thorouhly using competition experiments, CRBN KO (CRBN is recruited as E3 ligase) as well as by utilization of control compounds with aborgated binding to CRBN. In summary, CST967 is very decent tool compound and has my recommendation to be used as a tool degrader to study biology of USP7 in cellular experiments.
(last updated:
8 Jul 2023 )
