Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation

J Med Chem. 2020 Jul 9;63(13):7243-7251. doi: 10.1021/acs.jmedchem.0c00475. Epub 2020 Jun 9.


Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its "undruggable" nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization. One of the scaffolds, represented by the compound LQZ-7, contains an undesirable labile hydrazone linker and a potentially nonfunctional furazanopyrazine ring that we attempted to eliminate in this study. We found one compound, 7I, that is more active than the parent compound, LQZ-7, and when given orally effectively inhibits xenograft tumor growth and induces survivin loss in tumors. These findings indicate that 7I with a stable linker and a quinoxaline ring can be used as a lead for further optimization of this novel class of survivin inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Hydrazones / chemistry
  • Male
  • Mice
  • PC-3 Cells
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Multimerization
  • Survivin / antagonists & inhibitors
  • Survivin / metabolism*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • BIRC5 protein, human
  • Hydrazones
  • Survivin
  • Proteasome Endopeptidase Complex