In vitro activity: Selonsertib (Also known as GS-4997) is a highly selective and potent once-daily orally available inhibitor of ASK1 (apoptosis signal-regulating kinase 1) with a pIC50 of 8.3±0.07. Selonsertib has potential anti-inflammatory, antineoplastic and anti-fibrotic activities and has been evaluated as an experimental treatment for diabetic nephropathy and kidney fibrosis. Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, Selonsertib was identified. Selonsertib displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

Kinase Assay: Selonsertib (Also known as GS-4997) is a highly selective and potent once-daily orally available inhibitor of ASK1 (apoptosis signal-regulating kinase 1) with a pIC50 of 8.3±0.07. Selonsertib (GS-4997) is a highly selective and potent once-daily oral ASK1 inhibitor that competes with ATP in the ASK1 catalytic kinase domain.

Cell Assay: An orally bioavailable inhibitor of apoptosis signal-regulating kinase 1 (ASK1), with potential anti-inflammatory, antineoplastic and anti-fibrotic activities. Upon oral administration, ASK1 inhibitor GS-4997 targets and binds to the catalytic kinase domain of ASK1 in an ATP-competitive manner, thereby preventing its phosphorylation and activation. This prevents the phosphorylation of downstream kinases, such as c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK). By preventing the activation of ASK1-dependent signal transduction pathways, GS-4997 prevents the production of inflammatory cytokines, down-regulates the expression of genes involved in fibrosis, suppresses excessive apoptosis and inhibits cellular proliferation