NMS-873 is a potent and specific small molecule allosteric inhibitor of the ATPase VCP/p97 (IC₅₀ ~0.03 µM), identified by a high-throughput screening. It is very selective (IC₅₀ >10 μM) against all of the AAA ATPases, HSP90 or the 53 kinases tested. Using photo-affinity labeling, structural analysis and mutagenesis, the binding site of NMS-873 was found to be a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. NMS-873 activated the unfolded protein response, interfered with autophagy, and induced cancer cell death. NMS-873 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-873 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