Discovery and Optimization of Anticancer Dibenzothiazepinones That Target the Ribosome Biogenesis Factor NVL

Abstract Using inducible forward genetics, we recently discovered a dibenzothiazepinone (1) with activity against cancer cells via inhibition of the ribosome biogenesis factor NVL (nuclear valosin-containing protein-like). Herein, we delineate a comprehensive structure−activity relationship (SAR) study that explores the structural space surrounding the dibenzothiazepinone scaffold. A series of 115 analogs were synthesized and evaluated for activity against the colorectal cancer cell line HCT116 and counter-screened against cells CRISPR engineered to express a compound-resistant mutation in NVL. Our initial medicinal chemistry-driven campaign focused on improving potency, metabolic stability, and in vivo exposure and clearance. A fluorescence polarization assay with recombinant human NVL established a correlation between NVL-binding and antiproliferative activity. Cryo-EM structures of human NVL with select inhibitors revealed a binding mode that is consistent with the SAR data. This study led to the in vivo analog 100 (MM927), which we reported to suppress tumor growth in vivo without detectable toxicity via targeting the NVL.