NI-42

The chemical probe NI-57, which is closely related to NI-42, inhibits BRPF1, BRD1, BRPF3 and is the preferred probe for these targets. Although NI-57 is not yet published, it is commercially available. Details for NI-57 are available on the SGC website http://www.thesgc.org/chemical-probes/NI-57.

NI-42 is a moderately potent BRPF1 inhibitor (exact potency unclear as it is assay format dependent, but presuming ITC is preferred format, KD ~40 nM) with moderate selectivity: ~6X selectivity over BRPF2, ~10X over BRD7, ~20-40X selectivity over BRPF3 and BRD9, and much greater selectivity over remaining BRD-containing proteins screened. GSK6853 (http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00092) would appear to be the preferred probe for cellular use, as it is more potent and selective. NI-42 may be the best in vivo tool available for models that require chronic dosing, however, as its pharmacokinetics was compatible with oral dosing, unlike GSK6853 (limited to IP dosing).

As other SAB members have pointed out, it is difficult to obtain a clear view on the suitability of this probe for cellular work. Different biochemical IC₅₀s are cited and whilst target engagement is demonstrated, no quantitative target engagement (IC₅₀) has been reported. It is thus not possible to say to which extent the target is likely inhibited at a given concentrations or if near-complete inhibition in cells can be achieved without affecting other class IV bromodomains. As other SAB members pointed out, improved probes have been published for this target, though this seems to be the only one with decent mouse PK making it potentially usable in vivo. However, it should be noted, that without quantitative target engagement data, it is difficult to determine the dose for in vivo experiments.