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

J Med Chem. 2017 Jan 26;60(2):627-640. doi: 10.1021/acs.jmedchem.6b01363. Epub 2017 Jan 12.

Abstract

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).

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Binding Sites
  • Cell Nucleus / metabolism
  • Dogs
  • HEK293 Cells
  • HeLa Cells
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Heterocyclic Compounds, Bridged-Ring / chemical synthesis
  • Heterocyclic Compounds, Bridged-Ring / chemistry
  • Heterocyclic Compounds, Bridged-Ring / pharmacology*
  • Humans
  • Imidazoles / pharmacology
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Mice
  • NF-kappa B p50 Subunit / metabolism
  • NF-kappa B p52 Subunit / metabolism
  • Oxazepines / chemical synthesis
  • Oxazepines / chemistry
  • Oxazepines / pharmacology*
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Signal Transduction / drug effects

Substances

  • 10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl)-N3-methyl-5,6-dihydroimidazo(1,2-d)(1,4)benzoxazepine-2,3-dicarboxamide
  • 10-fluoro-9-(3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl)-2,5-diazatetracyclo(11.1.1.0(2,6).0(7,12))pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide
  • 2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
  • Heterocyclic Compounds, 4 or More Rings
  • Heterocyclic Compounds, Bridged-Ring
  • Imidazoles
  • Isoxazoles
  • NF-kappa B p50 Subunit
  • NF-kappa B p52 Subunit
  • Oxazepines
  • Oxazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase