Zharp1-211 is a potent, selective, type II inhibitor of RIPK1 kinase with IC50 of 53 nM and binding Kd of 8.7 nM.
Zharp1-211 targets the ATP-binding pocket in RIPK1's inactive DLG (Asp156–Leu157–Gly158)-out kinase conformation.
Zharp1-211 is selective for RIPK1 kinase, does not inhibit RIPK3 and a panel of 468 kinases at 10 uM.
Zharp1-211 is highly potent for blocking TNF-induced necroptosis in human colon cancer HT-29 cells (EC50=4.6 nM).
Zharp1-211 efficiently inhibited p-RIPK1 and p-MLKL and necroptosis in intestinal organoids exposed to necroptotic stimuli.
Zharp1-211 also significantly reduced the transcription of Cxcl9, Cxcl10, CIITA, and H2-DMB1 as well as the expression of MHCII protein in IFN-γ-stimulated mouse intestinal organoids.
Zharp1-211 treatment (5mg/kg) significantly reduced the severity of graft-versus-host disease (GVHD), leading to improved overall survival rates, ameliorated haplo- identical B6 anti-BDF1 mouse model of GVHD, reduced GVH inflammation in the colon, small intestine, and liver and attenuated skin inflammation.