TMX-2172

TMX-2172 demonstrated potent degradation activity for CDK2 in some cell lines, but it also induced degradation of other proteins, such as CDK5 and AURKA. Additionally, the authors did not mention whether the degradation of ZNF692 would have a synergistic effect on cell growth inhibitory activity. Data on the cell growth inhibitory activity of the co-treatment with the appropriate CDK2 ligand part of TMX-2172 and PEG-linked pomalidomide would be needed to confirm the effect. Another important point to mention is that TMX-2172 should be used cautiously in other cell lines because the degradation effects on CDK5 and AURKA are not clear in these lines.

While selectivity was shown for this probe in OVCAR8 cells (5 µM for 6 h) as well as Jurkat cells (10 µM for 6 h), more extensive cell profiling, including lines and time points, could have been performed to show broad selectivity. A common cell line used in degrader work is the HEK-293 cell line. 10 µM treatment here for both 6 h as well as longer timepoints would have been worthwhile to show, as well as a comparison of CRBN levels across these 3 lines. To claim selectivity, a much broader panel of lines with comparable and high CRBN levels should be shown. Generally, another negative control via appending a structurally similar but non-binding CDK2 ligand (eg, removing an element of the hinge binding motif) is also important for PROTAC controls.

Including additional time points after treatment would be beneficial.