Identification of small molecules with selective cytotoxicity toward UGT3A2 KO cells

National Center For Advancing Translational Sciences

Investigators

Abstract

During this reporting period, our collaborator’s lab identified phenol containing compounds to be selectively cytotoxic to Ewing sarcoma cell lines following a screen done at Broad that is called Profiling Relative Inhibition Simultaneously in Mixtures (PRISM). To identify the protein target of relevance and biological mechanism, they did a CRISPR-Cas9 screen. This identified two proteins: 1) UGT3A2 and 2) SLC35B4 as being the proteins giving these molecules their selective cytotoxicity. When these genes were knocked out, the molecules did not have cytotoxicity anymore. The NCATS team completed a quantitative high-throughput screening (qHTS) campaign using our in-house annotated and chemically diverse libraries. This effort has led to the identification of new chemical series with selective cell-killing activity, providing fresh opportunities to further probe mechanism, validate potential targets, and expand the chemical space beyond the originally identified phenol-containing molecules.