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