WRN Helicase Inhibitor, NSC 19630

Toxicity: Standard Handling (A)

A cell-permeable maleimide compound selectively inhibits Werner syndrome WRN helicase activity (IC₅₀ = 20 µM) over its ATPase and exonuclease activities (19% and <10% inhibition, respectively, at 50 µM), while exhibiting no effect against the helicase activity of two other human RecQ family DNA helicases (RECQ1 and Werner syndrome BLM), Fanconi anemia group J helicase FANCJ, as well as three other E. coli helicases, RecQ, UvrD, and DnaB. The WRN-dependent antiproliferation activity of MIRA-1/NSC 19630 in HeLa 1.2.11 cultures (0% vs. 95% inhibition with or without siRNA-mediated WRN-depletion, respectively, after 48 h 3 µM treatment) is shown to be a direct result of apoptosis induction due to replication forks blockage (20-fold increase in PCNA foci staining after 72 h 2 µM treatment), enhanced DSB (17-fold increase in γ-H2AX foci staining after 72 h 2 µM treatment), and increased S-phase population (from 24% to 42% after 72 h 2 µM treatment). In some cells, MIRA-1/NSC 19630 appears to also exert its apoptotic effect, at least in part, by restoring DNA-binding and transactivation function of some, but not all, p53 mutants.

Aggarwal, M., et al. 2011. Proc. Natl. Acad. Sci USA108, 1525.
Bykov, V.J.N., et al. 2005. J. Biol. Chem.280, 30384.

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

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