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Probe
PPM-3 is in
the process of SERP review.
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commentary.
Potency assay (off target):
PPM-3 demonstrated outstanding kinase selectivity among more than 300 kinases at 500 nM in terms of kinase inhibition.
Potency assay, off target (cells):
The ligand component of PPM-3 may also target bromodomain-containing protein 4 (BRD4), doublecortin-like kinase 1 (DCLK1), and leucine-rich repeat kinase 2 (LRRK2). The proteins produced by A375 cells treated with PPM-3 at various concentrations for 12 h were assessed via Western blotting. PPM-3 degraded ERK5, but not BRD4, LRRK2 or DCLK1.
Degradation of ERK5 by PPM-3 begins within 2-4 hours and peaks at 12 hours.
Proteomics analysis was performed at a late time point (48 h) which therefore may include secondary effects.
The selectivity profile is relatively good considering that the biological assay has been performed with 0.5 uM compound which could skew the results of the selectivity profile presented in the paper.
(last updated:
20 Feb 2025 )
SERP+
Ratings
In Cell Rating
SERP+
Comments:
A potent degrader of ERK5 with DC50 and Dmax values of <45 nM and >80% respectively across a panel of five cell lines. Degradation was observed between 2-4h, reaching a maximum at 12 h and lasting >72 h. The mechanism was confirmed by proteasome (MG-132) and neddylation inhibition (MLN4924). The degrader demonstrated exceptional selectivity at 500 nM in vitro against a panel of 300 kinases. However, proteomics was performed at 48 h and reported only with GO and KEGG analysis, potentially also observing secondary effects and not reporting on degrader selectivity. Alternative PROTAC INY-06-061 reported in 10.1016/j.chembiol.2022.09.004 has proteomic selectivity data so this probe may be used for orthogonal validation.
