Our recent study has shown that ubiquinol-cytochrome c reductase binding protein (UQCRB), the 13.4-kDa subunit of mitochondrial complex III, plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS)-mediated signaling. Here we report a new synthetic small molecule targeting the mitochondrial oxygen sensor UQCRB that was identified by pharmacophore-based virtual screening and in vitro and in vivo competition binding analyses. 6-((1-Hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho[1, 8-bc]thiophen-2-one (HDNT) binds to the hydrophobic pocket of UQCRB and potently inhibits in vitro angiogenesis of human umbilical vein endothelial cells without cytotoxicity. Furthermore, the binding of HDNT to UQCRB suppressed mitochondrial ROS-mediated hypoxic signal transduction. These results demonstrated that HDNT is a novel synthetic small molecule targeting UQCRB and exhibits anti-angiogenic activity by modulating the oxygen-sensing function of UQCRB.
Bibliographical noteFunding Information:
This work was supported by grants from the National Research Foundation of Korea Grant funded by the Korean Government (MEST) ( 2009-0092964 and 2010-0017984 ), the Translational Research Center for Protein Function Control, NRF ( 2009-0083522 ), the National R&D Program for Cancer Control ( 0620350 ), Ministry of Health & Welfare , and from the Brain Korea 21 project, Republic of Korea .
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry