Development of a novel class of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) modulators as promising antiangiogenic leads

Hye Jin Jung, Misun Cho, Yonghyo Kim, Gyoonhee Han, Ho Jeong Kwon

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Recently, we identified a novel therapeutic target and a small molecule for regulating angiogenesis. Our study showed that ubiquinol-cytochrome c reductase binding protein (UQCRB) of the mitochondrial complex III plays a crucial role in hypoxia-induced angiogenesis via mitochondrial reactive oxygen species (ROS) mediated signaling. Herein, we developed new synthetic small molecules that specifically bind to UQCRB and regulate its function. To improve the pharmacological properties of 6-((1-hydroxynaphthalen-4-ylamino)dioxysulfone)-2H-naphtho[1,8-bc]thiophen-2-one (HDNT), a small molecule that targets UQCRB, a series of HDNT derivatives were designed and synthesized. Several derivatives showed a significant increase in hypoxia inducible factor 1 (HIF-1) inhibitory potency compared to HDNT. The compounds bound to UQCRB and suppressed mitochondrial ROS-mediated hypoxic signaling, resulting in potent inhibition of angiogenesis without inducing cytotoxicity. Notably, one of these new derivatives significantly suppressed tumor growth in a mouse xenograft model. Therefore, these mitochondrial UQCRB modulators could be potential leads for the development of novel antiangiogenic agents.

Original languageEnglish
Pages (from-to)7990-7998
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number19
DOIs
Publication statusPublished - 2014 Oct 9

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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