UNC6934

UNC6934 is a well-characterized selective probe for Nuclear receptor-binding SET domain containing 2 (NSD2-PWWP1). NSD2 is the responsible for the dimethylation of lysine 36 of histone 3 and is overexpressed in multiple cancer types. UNC6934 binds to NSD2-PWWP1 with a Kd of 91 nM (SPR) and demonstrates excellent selectivity against other PWWP domains and methyltransferase domains. Cell-based activity (EC50 = 1.23 uM) was demonstrated using a NanoBRET assay with U2OS cells. No ADME or in vivo PK properties were reported so use of this probe should be limited to biochemical and cell-based assays until these properties have been establish.

UNC7142 offers a helpful probe to investigate the mechanisms and phenotypes of NSD2 inhibition in the cellular context. When used in parallel with the reported and closely related inactive control, the compound provides insight into NSD2 biology, which is of much interest to the epigenetic community. The probe is well characterised and profiled in this respect, but use in in vivo experiments, should be undertaken with caution - attributes around in vivo pharmacokinetics and pharmacodynamics have not been described and further characterisation would be required to support this utilisation.

This probe, as well as its control compound, has been rigorously assessed with orthogonal biochemical and cellular methods as the blocker of the PWWP domain of NDS2 in terms of target engagement and potential off-target effects. The users should note a few things upon using this compound for definitive outcomes. The mode of action of the probe is to bind the PWWP domain rather than other motifs of NSD2. The outcome of the probe should be interpreted in the context of the functions of NSD2's PWWP domain rather than human NSD2 in general. In addition, the cellular activity of the probe was examined with U2OS cells only. The cellular IC50 of the probe in other human cells may slightly vary.