SGC-CBP30

Users of this probe are advised to carefully consider the concentration range appropriate for their experiment. Although the recommendation states a 100-1000nM range in cells, pIC50 in a reporter assay is 1540nM (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183655/), and 2uM is used in a later publication (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553799/pdf/pnas.201501956.pdf); however profiles of activity appear to suggest that the weaker BRD activity may become significant at concentrations of 3.3 and 10 micromolar in cells (ibid), leaving a narrow window between on-target and off-target effects. Use of alternative probes for this target in parallel is recommended to aid deconvolution of possible BRD effects - use caution in interpreting results.

While the existing data suggest this is a high-quality probe, users should realize it was only screened versus 10 representatives within each BRD family, not the entire target class. Also, there is some activity versus GPCRs and PDEs: When tested against 136 GPCR, ion channel, enzyme, and kinase targets, compound 59 showed an IC₅₀ < 1 μM only for the adrenergic receptors α2C (0.11 μM) and α2A (0.57 μM), phosphodiesterase-5 (PDE5, 0.15 μM), and platelet-activating factor (PAF) (0.54 μM). In a human liver microsome (HLM) stability assay, no compound was detected after 60 min, implying that the metabolism of compound 59 may be too rapid for it to be useful as an oral in vivo probe.

SGC-CBP30 has BRD4(1) Kd of 850 nM; at 40-fold, this was the largest selectivity window over BET bromodomains reported until recently. BET-family bromodomain inhibitors have strong effects on cell proliferation and gene expression with IC50s similar to BET-binding affinity, making selectivity over this subfamily especially important for clean interpretation of biological results. Recently, an alternative CBP inhibitor, CPI-637 (http://dx.doi.org/10.1021/acsmedchemlett.6b00075), has stretched this window to ~700x BET selectivity, so it should be more suitable for distinguishing CBP-driven effects from BET, and it also has a negative enantiomer control. CPI-637 is not completely selective either, having 730 nM BRD9 affinity, but potent BRD9 chemical probes such as BI-9564 (http://dx.doi.org/10.1021/acs.jmedchem.5b01865) are available as controls, and their reported effects including on cell proliferation appear to be relatively modest compared to BET inhibitors of comparable affinity.