SID 487795

NSC 617145 is a selective werner syndrome helicase (WRN) helicase inhibitor with an IC50 value of 230 nM. NSC 617145 inhibits WRN ATPase, and induces double-strand breaks (DSB) and chromosomal abnormalities. NSC 617145 shows selective for WRN over BLM, FANCJ, ChlR1, RecQ, and UvrD helicases[1].

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA/RNA Synthesis

NSC 617145 (0.75-3 μM; 24-72 hours) shows maximal inhibition of proliferation (98%) at the lowest concentration in a WRN-specific manner in HeLa cells[1]. NSC 617145 (0.75 μM; 6 hours) induces WRN binding to chromatin and proteasomal degradation[1]. In FA-D2-/- cells, NSC 617145 (0.125 μM) acts synergistically with very low concentrations of Mitomycin C to inhibit proliferation in a WRN-dependent manner and induce double-strand breaks (DSB) and chromosomal abnormalities. NSC 617145 exposure results in enhanced accumulation of DNA-PKcs pS2056 foci and Rad51 foci in Mitomycin C-treated FA-deficient cells, suggesting that WRN helicase inhibition prevents processing of Rad51-mediated recombination products and activates NHEJ[1]. NSC 617145, induces cell cycle arrest and apoptosis in human T-cell leukemia virus type 1 (HTLV-1)-transformed adult T-cell leukemia cells[2]. Cell Viability Assay[1] Cell Line: HeLa cells Concentration: 0.75 μM, 1 μM, 1.5 μM, 2 μM, 3 μM Incubation Time: 24 hours, 48 hours, 72 hours Result: Inhibited cell proliferation in a WRN-specific manner. Western Blot Analysis[1] Cell Line: HeLa cells Concentration: 0.75 μM Incubation Time: 6 hours Result: Caused WRN to become degraded by a proteasome-mediated pathway.

[1]. Monika Aggarwal, et al. Werner syndrome helicase has a critical role in DNA damage responses in the absence of a functional fanconi anemia pathway. Cancer Res. 2013 Sep 1;73(17):5497-507.

[2]. R Moles, et al. WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells. J Hematol Oncol. 2016 Nov 9;9(1):121.