AChemical structure and docking model of Type II inhibitor 1 bound to the kinase domain of RIPK1 (PDB: 4NEU). The solvent-exposed group is highlighted in a yellow circle.BChemical structure and co-crystal structure of Type III inhibitor 2 in complex with RIPK1 (PDB: 6R5F). The solvent...
Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) ...
This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). Methods Patients with moderate to ...
Just one year ago, encouraging preclinical data saw GlaxoSmithKline kick-start a new clinical test of its investigational RIPK1 inhibitor GSK095. Now, the drug’s test in a tough-to-beat cancer has been axed. A brief line from its third-quarter financials posted this morning read: “GSK095 ...
Taken together, these data suggest that an RIPK1 inhibitor may present a novel therapeutic option to reduce the aberrant hyperinflammatory response and sepsis in the context of both viral and bacterial infections. Cerebral acute or ischaemic insults ...
This phase IIa, randomised, double-blind experimental medicine study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of the RIPK1 inhibitor GSK2982772 in patients with active UC. Design In part A, prior to a protocol amendment, one patient was ...
Nec-1a (Fig.1) is a highly selective RIPK1 inhibitor, which has often been used as a positive control in necroptosis-related studies45,46. The crystal structure of Nec-1a-RIPK1 complex shows that Nec-1a also induces very similar conformational change as RI-962 does and occupies (only) th...
necrosis factor (TNF) is a potent cytokine that has emerged as a critical therapeutic target in inflammatory diseases, including psoriasis2. However, despite the proven clinical efficacy of anti-TNF therapy, the mechanisms by which TNF triggers inflammation in these patients remain poorly understood....
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we sought to investigate whether autophagic inhibitor CQ could rescue C4-2B cell viability inhibition induced by SIM+MET treatment. Should CQ rescue viability, then autophagy is part of the cell death process induced by SIM+MET (i.e., autophagy-mediated necrotic cell death38), whereas lack of...