Shahid Rehan, Dale Tranter, Phillip P Sharp, Gregory B Craven, Eric Lowe, Janet L Anderl, Tony Muchamuel, Vahid Abrishami, Suvi Kuivanen, Nicole A Wenzell, Andy Jennings, Chakrapani Kalyanaraman, Tomas Strandin, Matti Javanainen, Olli Vapalahti, Matthew P Jacobson, Dustin McMinn, Christopher J Kirk, Juha T Huiskonen, Jack Taunton, Ville O Paavilainen
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis...
May 11, 2023: Nature Chemical Biology