GSK547

GSK547, a highly selective and potent RIP1 inhibitor, inhibits macrophage-mediated adaptive immune tolerance in pancreatic cancer[1].

Research Areas >> Cancer

Signaling Pathways >> Apoptosis >> RIP kinase

RIP1[1]

GSK547 (0.1-100000 nM; 24 hours) pretreats L929 cells with recombinant TNFα and zVAD at various doses for 30 min, then cell death is induced with an IC50 of 32 nM after 24 hours[1]. GSK547 up-regulates STAT1 signaling in bone marrow-derived macrophages (BMDM)[1]. Cell Viability Assay[1] Cell Line: L929 cells (Mouse L-cells NCTC 929) Concentration: 0.1 nM; 10 nM; 1000 nM; 100000 nM Incubation Time: 24 hours Result: Reduced viability of L929 cells after co-treatment with TNFα and zVAD with an IC50 of 32 nM. Western Blot Analysis[1] Cell Line: Bone marrow-derived macrophages (BMDM) Concentration: Incubation Time: 30 minutes Result: Up-regulated STAT1 signaling in BMDM.

GSK547 (GSK′547; RIP1i) robustly targets RIP1 in vivo. RIP1 inhibition results in immunogenic macrophage differentiation in pancreatic cancer, leading to adaptive immune activation and tumor protection for pancreatic ductal adenocarcinoma (PDA)[1]. GSK547 (100 mg/kg/day; fed via food-based dosing; 15-50 days) reduces tumor burden and extends survival compared with mice treated with controls or Nec-1s[1]. Animal Model: The wild-type (WT) mice orthotopically implanted with Pdx1Cre;KrasG12D;Trp53R172H (KPC)-derived tumor cells[1] Dosage: ~100 mg/kg Administration: Fed via food-based dosing, daily, 15-50 days Result: Reduced tumor burden and extended survival.

[1]. Wang W, et al. RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. Cancer Cell. 2018 Nov 12;34(5):757-774.e7.