Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

We report here structure-guided optimization
of a novel series
of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly
potent, low molecular weight lead, activity was improved by designing
a type 11/2 binding mode that accessed a back pocket past the methionine-471
gatekeeper. Divergent binding modes in NIK and PI3K were exploited
to dampen PI3K inhibition while maintaining NIK inhibition within
these series. Potent compounds were discovered that selectively inhibit
the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical
NF-κB1 (REL-A/p50).