Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

Xingqi Wang, Xuefeng Wu, Aihua Zhang, Shiyu Wang, Chunhui Hu, Wei Chen, Yan Shen, Renxiang Tan, Yang Sun, Qiang Xu
  • EBioMedicine, May 2016, Elsevier
  • DOI: 10.1016/j.ebiom.2016.03.042

Destruxin A5 Selectively Blocks PDGF-BB/PDGFR-ββ Signaling and Overcomes Liver Fibrosis

What is it about?

PDGF-BB/PDGFR-ββ signaling is a druggable target whose inhibition mitigates liver fibrosis severity. Currently approved medical therapies acting through PDGF-BB/PDGFR-ββ inhibition are based on multi-targeting tyrosine-kinase inhibitors. However, the structural similarity of the intracellular tyrosine kinase domain among receptor tyrosine kinases of class IV and V makes the design of a specific PDGFR-β-targeting small molecular weight the tyrosine-kinase inhibitors challenging. Fortunately and encouragingly, our present study shows that blockage of the interaction between PDGF-B and PDGFR-β by destruxin A5 could be an alternate pathway for PDGF-BB/PDGFR-ββ signaling inhibition. Additionally, destruxin A5 exhibited no direct interactions with human PDGFR-α, VEGFR1, VEGFR2, VEGFR3, FLT3, KIT, EGFR or IFN-γR1 and minimally inhibited the cell proliferation induced by PDGF-AA, VEGF, FLT3 ligand and KIT ligand. These findings suggest that destruxin A5 could be a potent and selective small-molecule inhibitor of the PDGF-BB/PDGFR-ββ signaling. Importantly, the selective inhibitory effect of destruxin A5 on PDGF-BB/PDGFR-ββ signaling carries extremely important clinical significance.

Why is it important?

Based on the above, our study is expected to contribute to the fundamental understanding of the potential therapeutic effects of destruxin A5 and to provide an approach for selectively inhibiting PDGF-BB/PDGFR-ββ signaling.

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The following have contributed to this page: Ph. D Xingqi Wang