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

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 TNF? induced lethal shock.

SUBMITTER: Harris PA

PROVIDER: S-EPMC4027519 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Harris Philip A PA Bandyopadhyay Deepak D Berger Scott B SB Campobasso Nino N Capriotti Carol A CA Cox Julie A JA Dare Lauren L Finger Joshua N JN Hoffman Sandra J SJ Kahler Kirsten M KM Lehr Ruth R Lich John D JD Nagilla Rakesh R Nolte Robert T RT Ouellette Michael T MT Pao Christina S CS Schaeffer Michelle C MC Smallwood Angela A Sun Helen H HH Swift Barbara A BA Totoritis Rachel D RD Ward Paris P Marquis Robert W RW Bertin John J Gough Peter J PJ

ACS medicinal chemistry letters 20131104 12

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. ...[more]

PMID: 24900635

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