2 research outputs found
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)
Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties
In our continued effort to discover
and develop best-in-class Bruton’s tyrosine kinase (Btk) inhibitors
for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic
lupus erythematosus, we devised a series of novel tricyclic compounds
that improved upon the druglike properties of our previous chemical
matter. Compounds exemplified by <b>G-744</b> are highly potent,
selective for Btk, metabolically stable, well tolerated, and efficacious
in an animal model of arthritis