TY - JOUR
T1 - Anticancer Pyrroloquinazoline LBL1 Targets Nuclear Lamins
AU - Li, Bingbing X.
AU - Chen, Jingjin
AU - Chao, Bo
AU - David, Larry L.
AU - Xiao, Xiangshu
N1 - Funding Information:
We thank S. Kaech and A. Snyder for technical help on fluorescence microscopy image acquisition and analysis. This work was supported by NIH R01CA211866 (X.X.) and partially by R01GM122820 (X.X.). Oregon Health & Science University School of Medicine, Office of the Technology Transfer and Business Development, Oregon Clinical and Translational Research Institute, Medical Research Foundation of Oregon and Lloyd Fund partially supported this research. Mass spectrometry was partially supported by NIH (through Grant Nos. P30EY010575 (L.L.D.), P30CA069533 (L.L.D.), and S10RR025571 (L.L.D.).
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/5/18
Y1 - 2018/5/18
N2 - Target identification of bioactive compounds is critical for understanding their mechanism of action. We previously discovered a novel pyrroloquinazoline compound LBL1 with significant anticancer activity. However, its molecular targets remain to be established. Herein, we developed a clickable photoaffinity probe based on LBL1. Using extensive chemical, biochemical, and cellular studies with this probe and LBL1, we found that LBL1 targets nuclear lamins, which are type V intermediate filament (IF) proteins. Further studies showed that LBL1 binds to the coiled-coil domain of lamin A. These results revealed that IF proteins can also be targeted with appropriate small molecules besides two other cytoskeletal proteins actin filaments and microtubules, providing a novel avenue to investigate lamin biology and a novel strategy to develop distinct anticancer therapies.
AB - Target identification of bioactive compounds is critical for understanding their mechanism of action. We previously discovered a novel pyrroloquinazoline compound LBL1 with significant anticancer activity. However, its molecular targets remain to be established. Herein, we developed a clickable photoaffinity probe based on LBL1. Using extensive chemical, biochemical, and cellular studies with this probe and LBL1, we found that LBL1 targets nuclear lamins, which are type V intermediate filament (IF) proteins. Further studies showed that LBL1 binds to the coiled-coil domain of lamin A. These results revealed that IF proteins can also be targeted with appropriate small molecules besides two other cytoskeletal proteins actin filaments and microtubules, providing a novel avenue to investigate lamin biology and a novel strategy to develop distinct anticancer therapies.
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U2 - 10.1021/acschembio.8b00266
DO - 10.1021/acschembio.8b00266
M3 - Article
C2 - 29648791
AN - SCOPUS:85047458306
SN - 1554-8929
VL - 13
SP - 1380
EP - 1387
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 5
ER -