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NMS-859 is a potent and specific small molecule covalent inhibitor of the ATPase VCP/p97 (IC₅₀ ~0.37 µM), identified by high-throughput screening. It is very selective (IC₅₀ >10 μM) against all of the AAA ATPases, HSP90 or the 53 kinases tested. NMS-859 was active in a cell proliferation assay, with IC₅₀ values of 3.5 μM and 3.0 μM in HCT116 and HeLa cell lines, respectively. NMS-859 covalently modifies VCP on the active site Cys522 and blocks ATP binding. NMS-859 provided critical validation of VCP as a cancer target, and it raises the possibility that targeting VCP might prevent proteasome inhibitor–resistant tumors from escaping through the aggresome-autophagy pathways and cause them to collapse under the high load of unfolded proteins.

How to Use: 

• In vitro:  NMS-859 was used at 2.5-10 µM final concentration in various in vitro assays.
• In vivo: n/a

Reference: 

1. 1. Magnaghi P, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. (2013) Nat Chem Biol. 9(9):548-56

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