Target discovery of selective non-small-cell lung cancer toxins reveals inhibitors of mitochondrial complex i

Nikhil Madhusudhan, Bin Hu, Prashant Mishra, Josè F. Calva-Moreno, Khushbu Patel, Richard Boriack, Joseph M. Ready, Deepak Nijhawan

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Selective toxicity among cancer cells of the same lineage is a hallmark of targeted therapies. As such, identifying compounds that impair proliferation of a subset of non-small-cell lung cancer (NSCLC) cell lines represents one strategy to discover new drugs for lung cancer. Previously, phenotypic screens of 202â »103 compounds led to the identification of 208 selective NSCLC toxins (McMillan, E. A., et al. Cell, 2018, 173, 864). The mechanism of action for the majority of these compounds remains unknown. Here, we discovered the target for a series of quinazoline diones (QDC) that demonstrate selective toxicity among 96 NSCLC lines. Using photoreactive probes, we found that the QDC binds to both mitochondrial complex I of the electron transport chain and hydroxyacyl CoA dehydrogenase subunit alpha (HADHA), which catalyzes long-chain fatty acid oxidation. Inhibition of complex I is the on-Target activity for QDC, while binding to HADHA is off-Target. The sensitivity profile of the QDC across NSCLC lines correlated with the sensitivity profiles of six additional structurally distinct compounds. The antiproliferative activity of these compounds is also the consequence of binding to mitochondrial complex I, reflecting significant structural diversity among complex I inhibitors. Small molecules targeting complex I are currently in clinical development for the treatment of cancer. Our results highlight complex I as a target in NSCLC and report structurally diverse scaffolds that inhibit complex I.

Original languageEnglish (US)
Pages (from-to)158-170
Number of pages13
JournalACS chemical biology
Volume15
Issue number1
DOIs
StatePublished - Jan 17 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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