Identification of effective anti-osteosarcoma agents via screening of an in-house NQO1-targeted compound library.

Osteosarcoma is one of the most prevalent malignant bone tumors, and despite advances in treatment, significant improvements in survival rates for osteosarcoma patients remain elusive. There is an urgent need for developing novel molecules for the targeted treatment of osteosarcoma. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly overexpressed in osteosarcoma. Here, we evaluated a series of in-house NQO1-targeting compounds, including NQO1 substrates and β-lap prodrugs, through phenotypic screening using NQO1-positive methylnitronitrosoguanidine-induced human osteosarcoma cells (MNNG) and NQO1-negative normal human umbilical vein endothelial cells (HUVEC), aiming to identify novel candidate compounds for osteosarcoma therapy. As a result, compound 21, an NQO1 substrate, was identified as a potent anti-osteosarcoma agent that promotes apoptosis and induces cell cycle arrest in osteosarcoma cells in vitro, while significantly inhibiting tumor growth in vivo. These findings suggest that compound 21 holds promise as a candidate for osteosarcoma treatment. Moreover, NQO1-targeting substrates present a promising pathway for the discovery of novel anti-osteosarcoma agents.