A novel small molecule that induces cytotoxicity in lung cancer cells inhibits disulfide reductases GSR and TXNRD1

ABSTRACT: Phenotype-based screening can identify unique small molecules that elicit a desired cellular response, but additional approaches are required to characterize their targets and mechanisms of action. Here we show that a compound termed LCS3, which selectively impairs the growth of human lung adenocarcinoma (LUAD) cells, induces oxidative stress. To identify the target that mediates this effect, we used thermal proteome profiling (TPP) and uncovered the disulfide reductases GSR and TXNRD1 as targets. We confirmed through enzymatic assays that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knockout screen identified NQO1 loss as a mechanism of LCS3 resistance. This work highlights the ability of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential therapeutic utility of inhibiting disulfide reductases in LUAD.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

SUBMITTER: Fraser Johnson  

LAB HEAD: William Lockwood

PROVIDER: PXD030294 | Pride | 2022-04-04

REPOSITORIES: Pride