Identification of the First Inhibitor of the GBP1:PIM1 Interaction. Implications for the Development of a New Class of Anticancer Agents Against Paclitaxel Resistant Cancer Cells

J Med Chem. 2014 Oct 9;57(19):7916-32. doi: 10.1021/jm5009902. Epub 2014 Sep 26.

Abstract

Class III β-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitaxel-resistant cells. Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling, and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site, the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Computational Biology
  • Drug Discovery
  • Drug Resistance, Neoplasm
  • GTP-Binding Proteins / antagonists & inhibitors*
  • GTP-Binding Proteins / chemistry
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Paclitaxel / pharmacology*
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / chemistry

Substances

  • Antineoplastic Agents
  • GBP1 protein, human
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • GTP-Binding Proteins
  • Paclitaxel