PID-34

In this paper, P1D-34 (the covalent Pin1 inhibitor Sulfopin linked to a cereblon ligand), induced potent Pin1 degradation with a DC50 value of 177 nM. The cellular IC50 varies between cells but is around 5uM on average. * Fig 3 with Pin1 KO, you see 50% cell death at 10uM. This suggests P1D-34 hits other targets at 10uM concentration, sufficient to drive the same phenotype, making interpretation of Pin1 biology in cells difficult at the 10uM concentration. * It would be good to see a comparison with Pin1 knock down to see what effect that has on cells and pathway proteins to see if similar to compound treatment. I'm concerned there are off-target effects driving some of the biology and it is hard to then use this as a probe to understand specific Pin1 biology.

While the authors have shown that PID-34 degrades PIN1 in the cellular setting, and that this is consistent with the expected mechanism for a PROTAC (proper mechanistic studies in the presence of neddylation inhibitor MLN4924 and proteasome inhibitor MG132) there is no information provided as to what else is degraded. Even with the includion of an inactive control compound the available data do not support the use of this PROTAC for selective assessment of the role of PIN1. To achieve this the authors need to add data using global proteomics - ideally at multiple concentrations to account also for the Hook effect (e.g. 0.1, 1, and 10 µM). Pending such data the usefulness is restricted to studies specifically around the degradation of PIN1, but not in drawing conclusions on functional consequences.