Journal
OPEN BIOLOGY
Volume 9, Issue 8, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsob.190117
Keywords
Mcm10; fluorescence polarization; suramin; RPA70; surface plasmon resonance
Categories
Funding
- University of Minnesota Medical School
- NIH [5R01 GM074917, R35 GM118089]
- NIH NIGMS [R35-GM118047]
- NIH ORIP [1S10OD021539]
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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 K-i 170 nM, SPR K-D 460 nM) and cell activity (IC50 38 mu M). 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.
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