The anti-parasitic agent suramin and several of its analogues are inhibitors of the DNA binding protein Mcm10

Carolyn N. Paulson, Kristen John, Ryan M. Baxley, Fredy Kurniawan, Kayo Orellana, Rawle Francis, Alexandra Sobeck, Brandt F. Eichman, Walter J. Chazin, Hideki Aihara, Gunda I. Georg, Jon E. Hawkinson, Anja Katrin Bielinsky

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Minichromosome maintenance protein 10 (Mcm10) is essential for DNA unwinding by the replisome during S phase. It is emerging as a promising anti-cancer target as MCM10 expression correlates with tumour progression and poor clinical outcomes. Here we used a competition-based fluorescence polarization (FP) high-throughput screening (HTS) strategy to identify compounds that inhibit Mcm10 from binding to DNA. Of the five active compounds identified, only the anti-parasitic agent suramin exhibited a dose-dependent decrease in replication products in an in vitro replication assay. Structure–activity relationship evaluation identified several suramin analogues that inhibited ssDNA binding by the human Mcm10 internal domain and full-length Xenopus Mcm10, including analogues that are selective for Mcm10 over human RPA. Binding of suramin analogues to Mcm10 was confirmed by surface plasmon resonance (SPR). SPR and FP affinity determinations were highly correlated, with a similar rank between affinity and potency for killing colon cancer cells. Suramin analogue NF157 had the highest human Mcm10 binding affinity (FP Ki 170 nM, SPR KD 460 nM) and cell activity (IC50 38 µM). Suramin and its analogues are the first identified inhibitors of Mcm10 and probably block DNA binding by mimicking the DNA sugar phosphate backbone due to their extended, polysulfated anionic structures.

Original languageEnglish (US)
Article number190117
JournalOpen biology
Volume9
Issue number8
DOIs
StatePublished - Aug 1 2019

Bibliographical note

Funding Information:
This work was supported by an Academic Health Center Faculty Research Development grant from the University of Minnesota Medical School and NIH grant no. 5R01 GM074917 to A.-K.B. This work was also supported by an NIH NIGMS grant no. R35-GM118047 to H.A., NIH ORIP grant no. 1S10OD021539 to J.E.H., and NIH grant no. R35 GM118089 to W.J.C.

Publisher Copyright:
© 2019 The Authors.

Keywords

  • Fluorescence polarization
  • Mcm10
  • RPA70
  • Suramin
  • Surface plasmon resonance

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