Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A)

Jonathan Seal; Yann Lamotte; Frédéric Donche; Anne Bouillot; Olivier Mirguet; Françoise Gellibert; Edwige Nicodeme; Gael Krysa; Jorge Kirilovsky; Soren Beinke; Scott McCleary; Inma Rioja; Paul Bamborough; Chun-Wa Chung; Laurie Gordon; Toni Lewis; Ann L Walker; Leanne Cutler; David Lugo; David M Wilson; Jason Witherington; Kevin Lee; Rab K Prinjha

doi:10.1016/j.bmcl.2012.02.041

Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A)

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2968-72. doi: 10.1016/j.bmcl.2012.02.041. Epub 2012 Feb 24.

Affiliation

¹ Epinova DPU, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK. [email protected]

PMID: 22437115
DOI: 10.1016/j.bmcl.2012.02.041

Abstract

A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.

MeSH terms

Animals
Binding Sites
Crystallography, X-Ray
Guinea Pigs
Heterocyclic Compounds, 4 or More Rings / chemistry*
Heterocyclic Compounds, 4 or More Rings / metabolism
Inflammation / drug therapy
Isoxazoles / chemical synthesis*
Isoxazoles / chemistry
Isoxazoles / pharmacology
Mice
Models, Molecular
Nerve Tissue Proteins / antagonists & inhibitors*
Protein Binding / drug effects
Quinolines / chemical synthesis*
Quinolines / chemistry
Quinolines / pharmacology
Rats

Substances

GSK1210151A
Heterocyclic Compounds, 4 or More Rings
Isoxazoles
Nerve Tissue Proteins
Quinolines