MLKL Degrader 1

MLKL Degrader 1 is currently the best compound available to study MLKL and its direct link to necroptosis in cells. Orthogonal compounds for investigating MLKL and necroptosis have been reported, however, direct target engagement of MLKL was never shown in assays. Therefore, the effect of necroptosis might be related to other targets in the signaling pathway such as RIPK1/3. MLKL Degrader 1 clearly shows RIPK1/3 independent and MLKL-driven proteosomal degradation of MLKL in HT29 cells. However, the concentration necessary for degradation with DC50 = 2.4 µM is quite high, and selectivity data such as kinome-wide screening and/or proteomics data are unavailable for this compound. When using this degrader, please carefully consider your results as off-target effects are unknown.

Selectivity profiling is required before this compound is considered for use as a probe for MLKL. It seems that rather a high concentration is required for full MLKL degradation, and at that high concentration it seems more likely that there would be other targets inhibited and/or degraded, but unfortunately, from what I can see, selectivity data was not obtained.

These doses are too high to be considered a useful probe compound - most degraders function at the low nM level in cells and at these doses it would not be unexpected that the probe may have off-target pharmacology that would be confusing. This probe needs to be orders of magnitude better to be a useful degrader.