TY - JOUR
T1 - Target discovery of selective non-small-cell lung cancer toxins reveals inhibitors of mitochondrial complex i
AU - Madhusudhan, Nikhil
AU - Hu, Bin
AU - Mishra, Prashant
AU - Calva-Moreno, Josè F.
AU - Patel, Khushbu
AU - Boriack, Richard
AU - Ready, Joseph M.
AU - Nijhawan, Deepak
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/1/17
Y1 - 2020/1/17
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.9b00734
DO - 10.1021/acschembio.9b00734
M3 - Article
C2 - 31874028
AN - SCOPUS:85077441845
SN - 1554-8929
VL - 15
SP - 158
EP - 170
JO - ACS chemical biology
JF - ACS chemical biology
IS - 1
ER -