Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis

  • ACS Med Chem Lett. 2013 Nov 4;4(12):1238-43. doi: 10.1021/ml400382p.
Philip A Harris  1 ,  Deepak Bandyopadhyay  1 ,  Scott B Berger  1 ,  Nino Campobasso  1 ,  Carol A Capriotti  1 ,  Julie A Cox  1 ,  Lauren Dare  1 ,  Joshua N Finger  1 ,  Sandra J Hoffman  1 ,  Kirsten M Kahler  2 ,  Ruth Lehr  1 ,  John D Lich  1 ,  Rakesh Nagilla  1 ,  Robert T Nolte  2 ,  Michael T Ouellette  1 ,  Christina S Pao  1 ,  Michelle C Schaeffer  1 ,  Angela Smallwood  1 ,  Helen H Sun  1 ,  Barbara A Swift  1 ,  Rachel D Totoritis  1 ,  Paris Ward  1 ,  Robert W Marquis  1 ,  John Bertin  1 ,  Peter J Gough  1
Affiliations
  • 1. Pattern Recognition Receptor DPU and Platform Technology & Science, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2. Platform Technology & Science, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
PMID: 24900635 DOI: 10.1021/ml400382p
Abstract

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.

Keywords
RIP1; necroptosis; type II kinase inhibitors.
Products