| 产品介绍 |
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鈥搑esistant tumors from escaping through the aggresome-autophagy pathways and cause them to collapse under the high load of unfolded proteins.
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