Therapeutics: Kinase suppressor of ras 2 (KSR2)

In vitro and cell culture studies identified a small molecule KSR2 stabilizer that could enhance the sensitivity of cancers to MAPK inhibitors. A screen of kinase inhibitors in a KSR2 binding assay identified a compound that competitively bound KSR2 with an IC50 of 120 nM and stabilized its inactive conformation. In a human colorectal cancer cell line harboring mutant K-Ras (KRAS), the compound plus the dual MAP kinase kinase 1 (MAP2K1; MEK1)/MAP2K2 (MEK2) inhibitor Mekinist trametinib decreased viability compared with Mekinist alone, and decreased the IC90 of Mekinist compared with vehicle. Next steps could include testing the compound in combination with Mekinist in animal models of cancer...