Paulson CN et al. (2019), The anti-parasitic agent suramin and several of...

XB-ART-56213

Open Biol 2019 Aug 30;98:190117. doi: 10.1098/rsob.190117.

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

Paulson CN , John K , Baxley RM , Kurniawan F , Orellana K , Francis R , Sobeck A , Eichman BF , Chazin WJ , Aihara H , Georg GI , Hawkinson JE , Bielinsky AK .

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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 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.

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Species referenced: Xenopus
Genes referenced: mcm10 rpa1 spr
GO keywords: DNA binding

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	Figure 1. Suramin inhibits DNA replication in an in vitro Xenopus replication assay. HTS hits were evaluated for inhibition of [α-32P]dGTP incorporation into DNA using a cell-free extract prepared from Xenopus eggs at increasing concentrations (10, 50, 150 and 300 µM indicated by black triangle from right to left). No chemical (–) and DMSO were used as negative controls for replication inhibition (far left and far right lanes).
	Figure 2. Structures of suramin and suramin analogues.
	Figure 3. Binding kinetics of suramin, NF023, NF546, and iso-PPADS to immobilized hMcm10-ID. Note the rapid association and dissociation of NF023 in contrast to the slow on- and off-rates of iso-PPADS. NF546 displays slow and rapid components in both the association and dissociation phases, whereas suramin has predominantly rapid kinetics. Each figure is a representative SPR sensorgram from one of more than three experiments.
	Figure 4. The slow binding inhibitor iso-PPADS competes with the fast binder NF023 for the same site on Mcm10. Representative sensorgrams of ABA SPR competition experiments (n > 3) in which injections of NF023 flank an injection of a ‘competitor’ compound: (a) running buffer, (b) NF023 self-competition, (c) suramin, or (d) iso-PPADS with and without NF023 at 10× KD. Note that a KD concentration of NF023, suramin, and iso-PPADS produce the expected RU in the B phase (black line), but none produce a greater response than a 10× KD concentration of NF023 alone (green line in B phase compared to A phases), indicating that they compete with NF023 for the same site.

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Ahmed, A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers. 2016, Pubmed