CZH-Z16

The cellular effects on biological pathways is ~3logs weaker than the degradation effects in the same cells. No proteomics data (and few other data) are supplied to show that the cell biology is only derived from target protein degradation. Until additional characterization of the key compounds' effects on proteins other than HDAC8 are available, the compound should be used with caution in experiments further describing effects that could be due to off targets.

This compound is among the most potent HDAC8 degraders currently available. A limitation for full recommendation as a cellular probe for HDAC8 is the current lack of global proteomics data to confirm selectivity for HDAC8 degradation in an unbiased manner.

This degrader lacks robust selectivity data, i.e. no proteomic data are shown, and selectivity has only been assessed against other Class I HDACs. While selectivity is shown through Western Blots within this family, it does not provide any insight into other off-target effects. Studies on the mechanism of action are also limited, missing proof of ternary complex formation. There is a competition study where cells were treated with a known HDAC8 inhibitor after pre-treatment with this probe and inhibitor activity decreased. However, no direct measurements are provided. It is positive that structural modifications to the probe have been introduced to produce two inactive controls (one inactive HDAC8 inhibitor, one inactive CRBN targeting PROTAC). Overall, the limited data means other probes that have been evaluated for HDAC8 would be a better choice.