molecules of the month

Kinase inhibitors are increasingly being explored for diseases beyond cancer. While SGK1 has been a cancer target, SGK1 has also been implicated in osteoarthritis pathology, and the Sanofi team developed “compound 17a” to interrogate this. The starting point was identified from ligand-based virtual screening, focusing on the DFG-out conformation, using models built from other SGK1 inhibitors. The pyrazole heterocycle is a two-point hinge binder. Library expansion and further optimization allowed the team to address aryl sulfonamide photostability, selectivity, permeability, and mutagenicity issues leveraging different parts of the molecule. Biological proof of concept was achieved using a mouse femoral head cartilage explant model in which cartilage sections are taken from mice and treated with drug. Significantly reduced disease biomarker (collagen type…